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Amlodipine — A study was conducted to assess the interaction of amlodipine (5 mg daily) and tadalafil 10 mg. There was no effect of tadalafil on amlodipine blood levels and no effect of amlodipine on tadalafil blood levels. The mean reduction in supine systolic/ diastolic blood pressure due to tadalafil 10 mg in subjects taking amlodipine was 3/ 2 mm Hg, compared to placebo. In a similar study using tadalafil 20 mg, there were no clinically significant differences between tadalafil and placebo in subjects taking amlodipine. Metoprolol — Text Continues Below
A study was conducted to assess the interaction of sustained-release metoprolol (25 to 200 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/ diastolic blood pressure due to tadalafil 10 mg in subjects taking metoprolol was 5/ 3 mm Hg, compared to placebo. Bendrofluazide — A study was conducted to assess the interaction of bendrofluazide (2.5 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/ diastolic blood pressure due to tadalafil 10 mg in subjects taking bendrofluazide was 6/ 4 mm Hg, compared to placebo. Enalapril — A study was conducted to assess the interaction of enalapril (10 to 20 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/ diastolic blood pressure due to tadalafil 10 mg in subjects taking enalapril was 4/ 1 mm Hg, compared to placebo. Angiotensin II receptor blocker (and other anti-hypertensives) — A study was conducted to assess the interaction of angiotensin II receptor blockers and tadalafil 20 mg. Subjects in the study were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination product, or as part of a multiple anti-hypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between tadalafil and placebo of 8/ 4 mm Hg in systolic/ diastolic blood pressure. Aspirin Tadalafil did not potentiate the increase in bleeding time caused by aspirin. Carcinogenesis, Mutagenesis, Impairment of Fertility Tadalafil 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 tadalafil, 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. Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil 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 tadalafil up to 400 mg/ kg/ day, a dose producing AUCs for unbound tadalafil 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 tadalafil 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 spermatogenesis 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 tadalafil 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. In men, there were no clinically relevant effects on sperm concentration, sperm count, motility, or morphology in placebo-controlled studies of daily doses of tadalafil 10 mg (N= 204) or 20 mg (N= 217) for 6 months. In addition, tadalafil had no effect on serum levels of testosterone, luteinizing hormone, or follicle stimulating hormone in males. Animal Toxicology Animal studies showed vascular inflammation in tadalafil-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 tadalafil 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 tadalafil 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 tadalafil 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. Pregnancy, Nursing Mothers, and Pediatric Use CIALIS is not indicated for use in newborns, children, or women. Tadalafil and/ or its metabolites cross the placenta, resulting in fetal exposure in rats. Tadalafil and/ or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma. Following a single-oral dose of 10 mg/ kg, approximately 0.1% of the total radioactive dose was excreted into the milk within 3 hours. It is not known if tadalafil and/ or its metabolites is excreted in human breast milk. Use of tadalafil in nursing mothers is not recommended. Pregnancy Category B — There was no evidence of teratogenicity, embryotoxicity, or fetotoxicity in rat or mouse fetuses that received up to 1000 mg/ kg/ day during the major organ development. Plasma exposure at this dose is approximately 11-fold greater than the AUC values for unbound tadalafil in humans given the MRHD of 20 mg. In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/ kg, there was a reduction in postnatal survival of pups. The no-observed-effect-level (NOEL) for maternal toxicity was 200 mg/ kg/ day and for developmental toxicity was 30 mg/ kg/ day, which gives approximately 16-and 10-fold exposure multiples, respectively, of the human AUC for the MRHD dose of 20 mg. There are no adequate and well-controlled studies of tadalafil in pregnant women. Geriatric Use Approximately 25% of patients in the primary efficacy and safety studies of tadalafil were greater than 65 years of age. No overall differences in efficacy and safety were observed between older and younger patients. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered (see Special Populations under CLINICAL PHARMACOLOGY).
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