itro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.
There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg t.i.d.
Pregnancy
Pregnancy Category B. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in pregnant rats or rabbits, dosed with 200 mg sildenafil/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 68-times, respectively, the RHD of 20 mg t.i.d. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). There are no adequate and well-controlled studies of sildenafil in pregnant women.
Nursing Mothers
It is not known if sildenafil citrate and/or metabolites are excreted in human breast milk. Since many drugs are excreted in human milk, caution should be used when REVATIO is administered to nursing women.
Pediatric Use
Safety and Effectiveness of sildenafil in pediatric pulmonary hypertension patients has not been established.
Geriatric Use
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, but studies did not include sufficient numbers of subjects to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger pulmonary arterial hypertension patients. 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.
ADVERSE REACTIONS
Safety data were obtained from the pivotal study and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. Doses up to 80 mg t.i.d. were studied. The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg t.i.d. was low (3%) and the same as placebo (3%).
In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that were reported by at least 3% of REVATIO patients treated at the recommended dosage (20 mg t.i.d.) and were more frequent in REVATIO patients than placebo patients, are shown in Table 2. Adverse events were generally transient and mild to moderate in nature.
Table 2. Sildenafil Adverse Events in >/=3% of Patients and More Frequent than Placebo
ADVERSE EVENT
% |
Placebo
(n=70) |
Sildenafil 20 mg t.i.d.
(n=69) |
Placebo
Subtracted |
|
Epistaxis |
1 |
9 |
8 |
|
Headache |
39 |
46 |
7 |
|
Dyspepsia |
7 |
13 |
6 |
|
Flushing |
4 |
10 |
6 |
|
Insomnia |
1 |
7 |
6 |
|
Erythema |
1 |
6 |
5 |
|
Dyspnea exacerbated |
3 |
7 |
|
