Sildenafil (Page 4 of 8)

8.5 Geriatric Use

Clinical studies of sildenafil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger 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 [see Clinical Pharmacology (12.3)] .

8.6 Patients with Hepatic Impairment

No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal Impairment

No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

11 DESCRIPTION

Sildenafil tablets USP, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® for erectile dysfunction.

Sildenafil citrate is designated chemically as 1-[[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-1 H- pyrazolo[4,3- d ]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:

Sildenafil Citrate Structural Formula
(click image for full-size original)

Sildenafil citrate, USP is a white to off-white powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.70.

Sildenafil Tablets: Sildenafil tablets are formulated as blue, film-coated, oval, unscored tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, FD&C Blue No. 2 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)] .

In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

12.2 Pharmacodynamics

Effects of Sildenafil on Hemodynamic Measures

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.

Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [Mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group
mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate
*
The number of patients per treatment group varied slightly for each parameter due to missing assessments.

Placebo

(n = 65) *

Sildenafil 20 mg

Three Times a Day

(n = 65) *

mPAP (mmHg)

0.6 (-0.8, 2.0)

-2.1 (-4.3, 0.0)

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)

In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)] , there were no significant differences in the effects on hemodynamic variables between doses.

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