CLONIDINE patch nonclinical toxicology

# Nonclinical Toxicology
In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for 6 months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid.
In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged.
In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

### Carcinogenesis, Mutagenesis, Impairment of Fertility
Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 to 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.
Fertility of male and female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times the MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis).

### Pregnancy
Teratogenic Effects
Pregnancy Category C
Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1 to 14 (lowest dose employed in the study was 500 mcg/kg).
No adequate well controlled studies have been conducted in pregnant women. Clonidine crosses the placental barrier (See CLINICAL PHARMACOLOGY:Pharmacokinetics). Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

### Nursing Mothers
As clonidine is excreted in human milk, caution should be exercised when Clonidine Transdermal System is administered to a nursing woman.

### Pediatric Use
Safety and effectiveness in pediatric patients have not been established in adequate and well controlled trials.