Cialis nonclinical toxicology
Cialis Carcinogenesis, Mutagenesis, Impairment of Fertility
Cialis was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound Cialis, were approximately 10-fold for mice, and 14- and 26-fold for male and female rats, respectively, the exposures in human males given Maximum Recommended Human Dose (MRHD) of 20 mg.
Cialis was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Cialis was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.
There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of Cialis up to 400 mg/kg/day, a dose producing AUCs for unbound Cialis of 14-fold for males or 26-fold for females the exposures observed in human males given the MRHD of 20 mg. In beagle dogs given Cialis daily for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20-100% of the dogs that resulted in a decrease in spermatogen esis in 40-75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound Cialis was similar to that expected in humans at the MRHD of 20 mg.
There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.
Cialis Animal Toxicology and/or Pharmacology
Animal studies showed vascular inflammation in Cialis-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound Cialis exposure of 2- to 33-fold above the human exposure (AUCs) at the MRHD of 20 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound Cialis exposure of 1- to 54-fold above the human exposure (AUC) at the MRHD of 20 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound Cialis exposures of approximately 14- to 18-fold the human exposure at the MRHD of 20 mg. The abnormal blood-cell findings were reversible within 2 weeks upon removal of the drug.
Cialis Reproductive Toxicology Studies
Reproduction studies have been performed in rats and mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg and have revealed no evidence of impaired fertility or harm to the fetus due to Cialis. In addition, there was no evidence of teratogenicity, embryotoxicity, or fetotoxicity when Cialis was given to pregnant rats or mice at exposures up to 11 times the MRHD during the period of major organ development.
In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg. Cialis and/or its metabolites cross the placenta, resulting in fetal exposure in rats.
Cialis and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.
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