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New Zealand white rabbits were treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.2, 0.5, and 1.0 mg/kg/day, administered topical y for 24 hours a day while wearing Elizabethan col ars to prevent ingestion of the drug. There appeared to be increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid- induced fetal malformations in this species, at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 3 times the maximum human systemic dose of tretinoin after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE.
for total body surface area. In a repeat study of the highest topical dose (1.0 mg/kg/day) in Brief Summary
pregnant rabbits, these effects were not seen, but a few alterations that may be associated Retin-A Micro® (tretinoin gel) microsphere, 0.1% and 0.04% is a formulation containing 0.1% with tretinoin exposure were seen. Other pregnant rabbits exposed topical y for six hours to or 0.04%, by weight, tretinoin for topical treatment of acne vulgaris. This formulation uses 0.5 or 0.1 mg/kg/day tretinoin while restrained in stocks to prevent ingestion, did not show patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres any teratogenic effects at doses up to 17 times (1.0 mg/kg/day) the maximum human systemic (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, adjusted for total body surface area, but fetal resorptions were increased at 0.5 mg/kg. In addition, topical IMPORTANT NOTE: This information is a BRIEF SUMMARY of the complete prescribing
tretinoin in non Retin-A Micro (tretinoin gel) microsphere formulations was not teratogenic in information provided with the product and therefore should not be used as the basis
rats and rabbits when given in doses of 42 and 27 times the maximum human systemic dose for prescribing the product. This summary has been prepared by deleting information
after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total from the complete prescribing information such as certain text, tables, and references.
body surface area, respectively, (assuming a 50 kg adult applied a daily dose of 1.0 g of 0.1% The physician should be thoroughly familiar with the complete prescribing information
gel topical y). At these topical doses, however, delayed ossification of several bones occurred before prescribing the product.
in rabbits. In rats, a dose-dependent increase of supernumerary ribs was observed.
INDICATIONS AND USAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is
Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhu- indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the man primates. Tretinoin was teratogenic in Wistar rats when given oral y or topical y in doses use of this product in the treatment of other disorders have not been established.
greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total CONTRAINDICATIONS: This drug is contraindicated in individuals with a history of sensitivity
body surface area). However, variations in teratogenic doses among various strains of rats have reactions to any of its components. It should be discontinued if hypersensitivity to any of its been reported. In the cynomolgus monkey, which metabolical y is more similar to humans than other species in its handling of tretinoin, fetal malformations were reported for doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human PRECAUTIONS:
systemic dose normalized for total body surface area), although increased skeletal variations General:
were observed at al doses. Dose-related increases in embryolethality and abortion also were • The skin of certain individuals may become excessively dry, red, swol en, or blistered. If the reported. Similar results have also been reported in pigtail macaques.
degree of irritation warrants, patients should be directed to temporarily reduce the amount Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence or frequency of application of the medication, discontinue use temporarily, or discontinue for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater use al together. Efficacy at reduced frequencies of application has not been established. than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface If a reaction suggesting sensitivity occurs, use of the medication should be discontinued. area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have Excessive skin dryness may also be experienced; if so, use of an appropriate emol ient also been reported when 10 mg/kg/day was topical y applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topical y or oral y with retinoids.
• Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, and patients with sunburn should There are no adequate and wel -control ed studies in pregnant women. Retin-A Micro should be be advised not to use the product until ful y recovered because of heightened susceptibility to used during pregnancy only if the potential benefit justifies the potential risk to the fetus. sunlight as a result of the use of tretinoin. Patients who may be required to have considerable With widespread use of any drug, a smal number of birth defect reports associated temporal y sun exposure due to occupation and those with inherent sensitivity to the sun should exercise with the administration of the drug would be expected by chance alone. Thirty human cases particular caution. Use of sunscreen products (SPF 15) and protective clothing over treated of temporal y associated congenital malformations have been reported during two decades of areas are recommended when exposure cannot be avoided. clinical use of Retin-A. Although no definite pattern of teratogenicity and no causal association • Weather extremes, such as wind or cold, also may be irritating to patients under treatment has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The • Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, should be kept away from the significance of these spontaneous reports in terms of risk to the fetus is not known.
eyes, the mouth, paranasal creases of the nose, and mucous membranes. Non-Teratogenic Effects: Topical tretinoin has been shown to be fetotoxic in rabbits when
• Tretinoin has been reported to cause severe irritation on eczematous skin and should be used administered 0.5 mg/kg/day (8 times the maximum human systemic dose applied topical y and with utmost caution in patients with this condition.
normalized for total body surface area), resulting in fetal resorptions and variations in ossifica- tion. Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased Information for Patients: A Patient Information Leaflet has been prepared and is included with
intrauterine death in rats when administered 2.5 mg/kg/day (21 times the maximum human each package of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. systemic dose applied topical y and normalized for total body surface area).
Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers,
products that have a strong drying effect, products with high concentrations of alcohol, astringents, There are, however no adequate and wel -control ed studies in pregnant women.
or spices should be used with caution because of possible interaction with tretinoin. Avoid contact Animal Toxicity Studies: In male mice treated topical y with Retin-A Micro (tretinoin gel)
with the peel of limes. Particular caution should be exercised with the concomitant use of topical microsphere 0.1%, at 0.5, 2.0, or 5.0 mg/kg/day tretinoin (2, 8, or 21 times the maximum over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, with Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. It also is advisable to al ow the 0.1%, normalized for total body surface area) for 90 days, a reduction in testicular weight, but effects of such preparations to subside before use of Retin-A Micro (tretinoin gel) microsphere, with no pathological changes were observed at the two highest doses. Similarly, in female mice there was a reduction in ovarian weights, but without any underlying pathological changes, at Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 91-week dermal study in which
5.0 mg/kg/day (21 times the maximum human dose). In this study there was a dose-related CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squa- increase in the plasma concentration of tretinoin 4 hours after the first dose. A separate toxi- mous cel carcinomas and papil omas in the treatment area were observed in some female cokinetic study in mice indicates that systemic exposure is greater after topical application to mice. These concentrations are near the tretinoin concentration of these clinical formulations unrestrained animals than to restrained animals, suggesting that the systemic toxicity observed (0.04% and 0.1%). A dose-related incidence of liver tumors in male mice was observed at is probably related to ingestion. Male and female dogs treated with Retin-A Micro (tretinoin gel) those same doses. The maximum systemic doses associated with the administered 0.017% microsphere, 0.1%, at 0.2, 0.5, or 1.0 mg/kg/day tretinoin (5, 12, or 25 times the maximum and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, four times the maximum human systemic dose applied topical y, when normalized for total 0.1%, normalized for total body surface area, respectively) for 90 days showed no evidence of body surface area. The biological significance of these findings is not clear because they reduced testicular or ovarian weights or pathological changes. occurred at doses that exceeded the dermal maximal y tolerated dose (MTD) of tretinoin and Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
because they were within the background natural occurrence rate for these tumors in this drugs are excreted in human milk, caution should be exercised when Retin-A Micro (tretinoin strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of gel) microsphere, 0.1% or 0.04%, is administered to a nursing woman.
tretinoin was administered topical y to mice (0.1 times the maximum human systemic dose, normalized for total body surface area). For purposes of comparisons of the animal exposure Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established.
to systemic human exposure, the maximum human systemic dose applied topical y is defined Geriatric Use: Safety and effectiveness in a geriatric population have not been established.
as 1 gram of Retin-A Micro (tretinoin gel) microsphere, 0.1% applied daily to a 50 kg person Clinical studies of Retin-A Micro did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dermal carcinogenicity testing has not been performed with Retin-A Micro (tretinoin gel) ADVERSE REACTIONS:
The skin of certain sensitive individuals may become excessively red, edematous, blistered, or Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the crusted. If these effects occur, the medication should either be discontinued until the integrity tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not However, efficacy has not been established for lower dosing frequencies. overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance True contact al ergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopig- of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial mentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse OVERDOSAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is intended for topical
micronucleus assay, both of which were negative.
use only. If medication is applied excessively, no more rapid or better results wil be obtained and The components of the microspheres have shown potential for genetic toxicity and teratogenesis. marked redness, peeling, or discomfort may occur. Oral ingestion of large amounts of the drug EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural may lead to the same side effects as those associated with excessive oral intake of Vitamin A.
chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cel s in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, the HGPRT forward mutation assay, and the mouse micronucleus assay.
Patent Nos.: 4,690,825; 5,145,675 & 5,955,109 In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statisti- cal y significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose applied topical y, and normalized for total body surface area), and slight (not statistical y significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose applied topical y and normalized for total body surface area) and above were observed. In oral Segment I and Segment I I studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (17 times the human topical dose normalized for total body surface area).
Dermal fertility and perinatal development studies with Retin-A Micro (tretinoin gel) microsphere, 0.1% or 0.04%, have not been performed in any species.
Pregnancy: Teratogenic Effects: Pregnancy Category C.
DIVISION OF ORTHO-MCNEIL PHARMACEUTICAL, INC. In a study of pregnant rats treated with topical application of Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.5 to 1 mg/kg/day on gestation days 6-15 (4 to 8 times the maximum human systemic dose of tretinoin normalized for total body sur- face area after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%) RETIN-A MICRO® is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.
some alterations were seen in vertebrae and ribs of offspring. In another study, pregnant MICROSPONGE® is a registered trademark of Cardinal Health, Inc., Dublin, OH.

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