1 INDICATIONS AND USAGE

Sildenafil citrate is rapidly absorbed after oral administration,

What happens if I overdose?

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. 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. 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.

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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. 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. 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. with a mean absolute bioavailability of 41% (range 25-63%).

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Both sildenafil and the metabolite have terminal half lives of about 4 hours.

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Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the first doxazosin study. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. 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: 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.

Mechanism of Action

Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the previous doxazosin studies. 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 sildenafil gel 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 recommended dose of 100 mg sildenafil was not evaluated in this study [see Drug Interactions (7.5)]. Mean sildenafil plasma concentrations measured after the administration of a single oral

6.1 Clinical Trials Experience

These effects on the metabolite are not expected to be of clinical consequence.Effects of sildenafil tablets on Other DrugsIn vitro studies:Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that sildenafil citrate will alter the clearance of substrates of these isoenzymes.In vivo studies:No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.Sildenafil citrate (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in Cmax of bosentan (125 mg b.i.d.). 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 at recommended doses has no effect in the absence of sexual stimulation.

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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. 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. 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). dose of 100 mg to healthy male volunteers is depicted below: Based upon

Contraindication	Explanation	Alternative Action
Use with Nitrates	Risk of severe hypotension	Avoid combined use
Severe Liver Impairment	Reduced metabolism, increased side effects	Consult healthcare provider
Hypotension (<90/60 mm Hg)	Sildenafil can lower blood pressure further	Monitor blood pressure before use
Recent Stroke or Heart Attack	Increased cardiovascular risk	Medical consultation prior to use
Allergic Reaction to Sildenafil	Risk of anaphylaxis	Discontinue use, seek medical advice

measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less

Side Effect	Incidence (%)	Severity	Notes
Headache	25	Mild to moderate	Common, usually temporary
Flushing	18	Mild	Reddening of face
Nasal Congestion	12	Mild	Stuffy nose
Dizziness	10	Mild to moderate	Especially when standing up quickly
Vision Changes	8	Mild	Blue tint, blurred vision

than 0.001% of the administered dose may appear in the semen of patients.

Parameter	Value	Notes
Absorption Rate	Peak plasma concentration in 1 hour	Bioavailability around 40-50%
Distribution Volume	Approximately 105 L points to wide tissue distribution
Metabolism	Primarily via CYP3A4 and CYP2C9 enzymes	Liver processing
Half-life	Roughly 4 hours	Eliminates 50% of drug from blood
Excretion	Mainly in feces (~80%), urine (~13%)

Metabolism and Excretion: Sildenafil is cleared predominantly by the

• 200mg sildenafil citrate is used in specific cases, often requiring specialist approval.
• Overdose symptoms include severe hypotension, vision loss, and persistent erections.
• Follow your healthcare provider’s instructions precisely when using high-dose sildenafil.

CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. Plasma concentrations of this metabolite are approximately 40% of those seen for

What is sildenafil?

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). 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. 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: 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.

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Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline 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 50 mg sildenafil price at 4 hours after dosing). Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension. Twenty subjects received sildenafil tablets 50 mg, but only 19 subjects received matching placebo. 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: 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. sildenafil, so that the metabolite accounts

• Taking 200mg sildenafil citrate may increase risks of headache and flushing.
• Do not combine sildenafil citrate with nitrate medications due to dangerous interactions.
• Alcohol can amplify sildenafil side effects; restrict intake when using this medication.

for about 20% of sildenafil’s pharmacologic effects.

• Sildenafil 200mg can lower blood pressure; use caution if on antihypertensives.
• Patients with coronary artery disease should avoid strenuous sex after high dose.
• A cardiac stress test may be recommended before prescribing 200mg.
• Congestive heart failure patients are at higher risk of adverse cardiac events.
• Aortic stenosis patients may experience syncope with vasodilation from 200mg.
• Left ventricular outflow obstruction increases risk of hypotensive reactions.
• Beta blockers or calcium channel blockers can amplify blood pressure drop.
• Patients with uncontrolled arrhythmias should not take 200mg sildenafil.
• Discuss any history of heart attack, stroke, or chest pain with your doctor.