Sildenafil Citrate (Page 4 of 8)

8.4 Pediatric Use

Sildenafil tablets are not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18-45 years) [see Clinical Pharmacology (12.3) ]. Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [see Clinical Pharmacology (12.3) ].

Of the total number of subjects in clinical studies of sildenafil tablets, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects.

However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [see Dosage and Administration (2.5) ].

8.6 Renal Impairment

No dose adjustment is required for mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr<30 mL/min), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (~2 fold), approximately doubling of C_max and AUC. A starting dose of 25 mg should be considered in patients with severe renal impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C_max and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied. A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence 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, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Sildenafil citrate USP 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:

Sildenafil citrate USP 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 tablets, USP are formulated as green, oval-shaped, beveled edge, biconvex, film-coated tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, FD & C Blue #1/brilliant blue FCF aluminum lake, D & C yellow # 10 aluminum lake.
FDA approved dissolution test specifications differ from USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.

Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.

Binding Characteristics Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [see Clinical Pharmacology (12.2) ].

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro , an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

12.2 Pharmacodynamics

Effects of sildenafil tablets on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan^®), after sildenafil tablets administration compared with placebo. Most studies assessed the efficacy of sildenafil tablets approximately 60 minutes post dose. The erectile response, as assessed by RigiScan^® , generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.

Effects of sildenafil tablets on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of sildenafil tablets, 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 (4.1) ].

Effects of sildenafil tablets on Blood Pressure When Nitroglycerin is Subsequently Administered: Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see Contraindications (4.1) ].

Effects of sildenafil tablets on Blood Pressure When Co-administered with Alpha-Blockers: Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of sildenafil tablets with doxazosin, an alpha-adrenergic blocking agent.

Study 1: Sildenafil tablets with Doxazosin In the first study, a single oral dose of sildenafil tablets 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, sildenafil tablets 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the sildenafil citrate dose was reduced to 25 mg. Thereafter, 17 subjects were treated with sildenafil tablets 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66.5 years.

For the 17 subjects who received sildenafil tablets 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	Sildenafil tablets 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg sildenafil tablets or matching placebo are shown in Figure 2.

Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline
Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after sildenafil tablets or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more timepoints. There were no subjects treated with sildenafil tablets 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following sildenafil tablets 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.

Of the four subjects who received sildenafil tablets 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with sildenafil tablets with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had a standing SBP < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension.

Study 2: Sildenafil tablets with Doxazosin In the second study, a single oral dose of sildenafil tablets 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, sildenafil tablets 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years.

Twenty subjects received sildenafil tablets 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with sildenafil tablets 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

For the 19 subjects who received both sildenafil tablets and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	Sildenafil tablets 50 mg (95% CI)
Supine	9.08 (5.48, 12.68)
Standing	11.62 (7.34, 15.90)

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil tablets or matching placebo are shown in Figure 3.

Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of sildenafil tablets 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30mmHg following sildenafil tablets 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.
Study 3: S ildenafil tablets with Doxazosin In the third study, a single oral dose of sildenafil tablets 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of sildenafil tablets 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using sildenafil tablets 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, sildenafil tablets 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years.

Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil tablets 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil tablets 50 mg).

For the 20 subjects who received sildenafil tablets 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	Sildenafil tablets 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil tablets or matching placebo are shown in Figure 4.

Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking sildenafil tablets 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil tablets 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil tablets 50 mg and 100 mg. There were no episodes of syncope reported in this study.

Effect of sildenafil tablets on Blood Pressure When Co-administered with Anti-hypertensives: When sildenafil tablets 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

Effect of sildenafil tablets on Blood Pressure When Co-administered with Alcohol: Sildenafil tablets (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports of postural dizziness or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see Drug Interactions (7.5)].

Effects of sildenafil tablets on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.

Studies have produced relevant data on the effects of sildenafil citrate on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions.

The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.
Table 3. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil

Means ± SD	At rest				After 4 minutes of exercise
	N	Baseline (B2)	n	Sildenafil (D1)	n	Baseline	n	Sildenafil
PAOP (mmHg)	8	8.1 ± 5.1	8	6.5 ± 4.3	8	36.0 ± 13.7	8	27.8 ± 15.3
Mean PAP (mmHg)	8	16.7 ± 4	8	12.1 ± 3.9	8	39.4 ± 12.9	8	31.7 ± 13.2
Mean RAP (mmHg)	7	5.7 ± 3.7	8	4.1 ± 3.7	–	–	–	–
Systolic SAP (mmHg)	8	150.4 ± 12.4	8	140.6 ± 16.5	8	199.5 ± 37.4	8	187.8 ± 30.0
Diastolic SAP (mmHg)	8	73.6 ± 7.8	8	65.9 ± 10	8	84.6 ± 9.7	8	79.5 ± 9.4
Cardiac output (L/min)	8	5.6 ± 0.9	8	5.2 ± 1.1	8	11.5 ± 2.4	8	10.2 ± 3.5
Heart rate (bpm)	8	67 ± 11.1	8	66.9 ± 12	8	101.9 ± 11.6	8	99.0 ± 20.4

In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil tablets 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of sildenafil tablets on the primary endpoint was statistically non-inferior to placebo.

Effects of sildenafil tablets on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination 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. Subjects in the study reported this finding as difficulties in discriminating blue/green. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil tablets on visual acuity, intraocular pressure, or pupillometry.

Effects of sildenafil tablets on Sperm: There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil tablets in healthy volunteers.