were observed with all doses of sildenafil. These increases were highly significantly different from placebo, but the dose groups were not different from each other (Figure 1). The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.
Pre-defined subpopulations in the pivotal study were also eva luated for efficacy, including patient differences in baseline walk distance, disease etiology, functional class, gender, age, and secondary hemodynamic parameters (Figure 2).
Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo. Doses of 20 mg, 40 mg, and 80 mg t.i.d. produced a placebo-corrected decrease in mPAP of -2.7 mmHg, -3.0 mmHg, and -5.1 mmHg, respectively. There was no evidence of a difference in effect between sildenafil 20 mg t.i.d. and the higher doses tested. Data from other hemodynamic parameters can be found in Table 1. The relationship between these effects and improvements in 6-minute walk distance is unknown.
Table 1. Changes from Baseline to Week 12 in Hemodynamic Parameters at Sildenafil 20 mg t.i.d. Dose
|
PARAMETER
[mean (95% CI)]
|
Placebo
(N=65) * |
Sildenafil 20 mg
t.i.d.
(N=65) * |
|
PVR (dyn·s/cm 5 )
|
49 (-54, 153) |
-122 (-217, -27) |
|
SVR (dyn·s/cm 5 )
|
-78 (-197, 41) |
-167 (-307, -26) |
|
RAP (mmHg)
|
0.3 (-0.9, 1.5) |
-0.8 (-1.9, 0.3) |
|
CO (L/min)
|
-0.1 (-0.4, 0.2) |
0.4 (0.1, 0.7) |
|
HR (beats/min)
|
-1.3 (-4.1, 1.4) |
-3.7 (-5.9, -1.4) |
|
*The number of patients per treatment group varied slightly for each parameter due to missing assessments. |
259 of the 277 treated patients entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously.
INDICATIONS AND USAGE
REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability.
The efficacy of REVATIO has not been eva luated in patients currently on bosentan therapy.
CONTRAINDICATIONS
Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY ), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated.
REVATIO is contraindicated in patients with a known hypersensitivity to any component of the tablet.
WARNINGS
The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A4 inhibitor) substantially increases serum concentrations of sildenafil, therefore co-administration with REVATIO is not recommended (see Drug Interactions and DOSAGE AND ADMINISTRATION ).
REVATIO has vasodilator properties, resulting in mild and transient decreases in bloo
