Sildenafil For Oral Suspension (Page 4 of 8)

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 for Oral Suspension, 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-1H -pyrazolo [4,3-d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:

Chemical Structure
(click image for full-size original)

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.

Sildenafil for Oral Suspension is supplied as white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil) in an amber glass bottle intended for reconstitution. Following reconstitution with 90 mL water, the volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive ingredients include sorbitol, citric acid anhydrous, sucralose, sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide anhydrous and grape flavor. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 0.5 mL and 2 mL dose markings) are provided.

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 for Oral Suspension on Hemodynamic Measures Patients on all Sildenafil for Oral Suspension 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 for Oral Suspension 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
Placebo(n = 65)* Sildenafil for OralSuspension 20 mgthree times a day(n = 65)*
*
The number of patients per treatment group varied slightly for each parameter due to missing assessments.
mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0)
PVR (dyn∙s/cm5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn∙s/cm5) -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)

mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance;
SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiacoutput; HR = heart rate

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.

Effects of Sildenafil for Oral Suspension on Blood Pressure

Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)].

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported.

After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively.

After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.

After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).

Effects of Sildenafil for Oral Suspension on Vision

At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of Sildenafil for Oral Suspension on visual acuity, intraocular pressure, or pupillometry.

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