In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased F3850, F3853, F3856, F3859, F3883, F3886, L5611, L5614. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased F3850, F3853, F3856, F3859, F3883, F3886, L5611, L5614.

Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures F3850, F3859, F3883, L5614.

The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied F3850, F3859, F3883, L5614. Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk F3850, F3859, F3883, L5614.

The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available ^F3883.

Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients ^F3850 while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients ^L5614. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy ^F3850.

Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed F3853, L5611. This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years) F3853, L5611. Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40% F3853, L5611.

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg F3850, F3853, F3856, F3859, F3883, F3886, L5611, L5614. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis F3850, F3853, F3856, F3859, F3883, F3886, L5611, L5614.

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity F3850, F3853, F3856, F3859, F3883, F3886, L5611, L5614.

There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC F3850, F3853, F3856, F3859, F3883, F3886, L5611, L5614.