PRECAUTIONS SECTION.

PRECAUTIONS. GeneralThe evaluation of erectile dysfunction should include determination of potential underlying causes and the identification of appropriate treatment following complete medical assessment.Before prescribing VIAGRA, it is important to note the following:Caution is advised when Phosphodiesterase Type (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly (see Drug Interactions) leading to symptomatic hypotension (e.g. dizziness, lightheadedness, fainting). Consideration should be given to the following:- Patients should be stable on alpha-blocker therapy prior to initiating PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose. In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs. Viagra has systemic vasodilatory properties and may augment the blood pressure lowering effect of other anti-hypertensive medications.Patients on multiple antihypertensive medications were included in the pivotal clinical trials for VIAGRA. In separate drug interaction study, when amlodipine, mg or 10 mg, and VIAGRA, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of mmHg systolic and mmHg diastolic were noted (see Drug Interactions ).The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration.VIAGRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronies disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).The safety and efficacy of combinations of VIAGRA with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.Information for PatientsPhysicians should discuss with patients the contraindication of VIAGRA with regular and/or intermittent use of organic nitrates.Physicians should advise patients of the potential for VIAGRA to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of VIAGRA and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when VIAGRA is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose.Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician.Physicians should advise patients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be sign of non-arteritic anterior ischemic optic neuropathy (NAION), cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors (see POST-MARKETING EXPERIENCE/Special Senses ).Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS, CLINICAL TRIALS and POST-MARKETING EXPERIENCE ).Physicians should warn patients that prolonged erections greater than hours and priapism (painful erections greater than hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.Physicians should inform patients not to take VIAGRA with other PDE5 inhibitors including REVATIO. Sildenafil is also marketed as REVATIO for the treatment of pulmonary arterial hypertension. The safety and efficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not been studied.The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered. Drug InteractionsEffects of Other Drugs on VIAGRAIn vitro studiesSildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.In vivo studiesCimetidine (800 mg), nonspecific CYP inhibitor, caused 56% increase in plasma sildenafil concentrations when coadministered with VIAGRA (50 mg) to healthy volunteers.When single 100 mg dose of VIAGRA was administered with erythromycin, specific CYP3A4 inhibitor, at steady state (500 mg bid for days), there was 182% increase in sildenafil systemic exposure (AUC). In addition, in study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also CYP3A4 inhibitor, at steady state (1200 mg tid) with VIAGRA (100 mg single dose) resulted in 140% increase in sildenafil Cmax and 210% increase in sildenafil AUC. VIAGRA had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) (see DOSAGE AND ADMINISTRATION ).In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (100 mg single dose) resulted in 300% (4-fold) increase in sildenafil Cmax and 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately ng/mL when sildenafil was dosed alone. This is consistent with ritonavirs marked effects on broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics (see DOSAGE AND ADMINISTRATION ).Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.In study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in 63% decrease of sildenafil AUC and 55% decrease in sildenafil Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA.Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.Effects of VIAGRA on Other DrugsIn vitro studiesSildenafil is weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 uM). Given sildenafil peak plasma concentrations of approximately uM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes.In vivo studiesThree double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blocking agent.In the first study, single oral dose of VIAGRA 100 mg or matching placebo was administered in 2-period crossover design to generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following review of the data from these first subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin mg (15 subjects) or doxazosin 8mg (2 subjects). The mean subject age was 66.5 years. For the 17 subjects who received VIAGRA 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)VIAGRA 25 mgSupine 7.4 (-0.9, 15.7) Standing 6.0 (-0.8, 12.8) Figure 5: 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, and hours after VIAGRA or matching placebo. Outliers were defined as subjects with standing systolic blood pressure of less than 85 mmHg or decrease from baseline in standing systolic blood pressure of greater than 30 mmHg at one or more timepoints. There were no subjects treated with VIAGRA 25 mg who had standing SBP less than 85mmHg. There were three subjects with decrease from baseline in standing systolic BP greater than 30mmHg following VIAGRA 25 mg, one subject with decrease from baseline in standing systolic BP greater than 30 mmHg following placebo and two subjects with decrease from baseline in standing systolic BP greater than 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.Of the four subjects who received VIAGRA 100 mg in the first part of this study, severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at hour after dosing; and dizziness, lightheadedness and nausea at 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 standing SBP less than 85mmHg. Both of these subjects were protocol violators, one due to low baseline standing SBP, and the other due to baseline orthostatic hypotension.In the second study, single oral dose of VIAGRA 50 mg or matching placebo was administered in 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50mg or matching placebo was administered simultaneously with doxazosin mg (17 subjects) or with doxazosin mg (3 subjects). The mean subject age in this study was 63.9 years.Twenty subjects received VIAGRA 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 VIAGRA 50 mg. This patient had been taking minoxidil, potent vasodilator, during the study.For the 19 subjects who received both VIAGRA 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)VIAGRA 50 mg (95% CI)Supine 9. (5.48, 12.68) Standing 11.62 (7.34, 15.90) Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline. Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had standing SBP of less than 85 mmHg. In these two subjects, hypotension was reported as moderately severe adverse event, beginning at approximately hour after administration of VIAGRA 50 mg and resolving after approximately 7.5 hours. There was one subject with decrease from baseline in standing systolic BP greater than 30mmHg following VIAGRA 50 mg and one subject with decrease from baseline in standing systolic BP greater than 30 mmHg following both VIAGRA 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.In the third study, single oral dose of VIAGRA 100 mg or matching placebo was administered in 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If 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 VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least days after dose period 1. Thereafter, VIAGRA 100mg or matching placebo was administered simultaneously with doxazosin mg (14 subjects) or doxazosin 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 moderately severe adverse event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg).For the 20 subjects who received VIAGRA 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)VIAGRA 100 mgSupine 7.9 (4.6, 11.1) Standing 4.3 (-1.8, 10.3) Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline. Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had standing SBP of less than 85 mmHg. All three were taking VIAGRA 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 decrease from baseline in standing systolic BP greater than 30mmHg following VIAGRA 100 mg, one subject with decrease from baseline in standing systolic BP greater than 30 mmHg following placebo and one subject with decrease from baseline in standing systolic BP greater than 30 mmHg following both VIAGRA 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 VIAGRA 50 mg and 100 mg. There were no episodes of syncope reported in this study.When VIAGRA 100 mg oral was coadministered with amlodipine, mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was mmHg systolic and mmHg diastolic.No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.In 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 at steady state (80 mg t.i.d.) resulted in 50% increase in AUC and 42% increase in Cmax of bosentan (125 mg b.i.d.).Carcinogenesis, Mutagenesis, Impairment of FertilitySildenafil was not carcinogenic when administered to rats for 24 months at dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42-times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on mg/m2 basis.Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, dose producing an AUC value of more than 25 times the human male AUC.There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers.Pregnancy, Nursing Mothers and Pediatric UseVIAGRA is not indicated for use in newborns, children, or women.Pregnancy Category BNo evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the MRHD on mg/m2 basis in 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat the AUC at this dose was about 20 times human AUC. There are no adequate and well-controlled studies of sildenafil in pregnant women.Geriatric UseHealthy elderly volunteers (65 years or over) had reduced clearance of sildenafil (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations ). Since higher plasma levels may increase both the efficacy and incidence of adverse events, starting dose of 25 mg should be considered (see DOSAGE AND ADMINISTRATION ).. image of figure (Mean Standing Systolic Blood Pressure). image of figure (Mean Standing Systolic Blood Pressure). image of figure (Mean Standing Systolic Blood Pressure).

SPL UNCLASSIFIED SECTION.

Absorption and DistributionVIAGRA is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with high fat meal, the rate of absorption is reduced, with mean delay in Tmax of 60 minutes and mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.Metabolism and ExcretionSildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafils pharmacologic effects. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using population pharmacokinetic approach.Pharmacokinetics in Special PopulationsGeriatricsHealthy elderly volunteers (65 years or over) had 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 younger volunteers (18-45 years). 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.Renal InsufficiencyIn volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr= less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.In addition, N-desmethyl metabolite AUC and Cmax values significantly increased 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function.Hepatic InsufficiencyIn volunteers with hepatic cirrhosis (Child-Pugh and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child Pugh class C) have not been studied.Therefore, age greater than 65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. starting oral dose of 25 mg should be considered in those patients (see DOSAGE AND ADMINISTRATION ).PharmacodynamicsEffects of VIAGRA on Erectile ResponseIn 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(R)), after VIAGRA administration compared with placebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post dose. The erectile response, as assessed by RigiScan(R), 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 hours but the response was diminished compared to hours.Effects of VIAGRA on Blood PressureSingle 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 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, 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 ).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of ActionThe 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 has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type (PDE5), which is responsible for degradation of cGMP in the 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.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). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because 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 observed with higher doses or plasma levels (see Pharmacodynamics ).In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.Pharmacokinetics and MetabolismVIAGRA is rapidly absorbed after oral administration, with mean absolute bioavailability of 41% (range 25-63%). Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. The concomitant use of potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil (see DOSAGE AND ADMINISTRATION ). Both sildenafil and the metabolite have terminal half lives of about hours.Mean sildenafil plasma concentrations measured after the administration of single oral dose of 100 mg to healthy male volunteers is depicted below:. Figure 1: Mean Sildenafil Plasma Concentrationsin Healthy Male Volunteers.. Absorption and DistributionVIAGRA is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with high fat meal, the rate of absorption is reduced, with mean delay in Tmax of 60 minutes and mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.Metabolism and ExcretionSildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafils pharmacologic effects. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using population pharmacokinetic approach.Pharmacokinetics in Special PopulationsGeriatricsHealthy elderly volunteers (65 years or over) had 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 younger volunteers (18-45 years). 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.Renal InsufficiencyIn volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr= less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.In addition, N-desmethyl metabolite AUC and Cmax values significantly increased 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function.Hepatic InsufficiencyIn volunteers with hepatic cirrhosis (Child-Pugh and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child Pugh class C) have not been studied.Therefore, age greater than 65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. starting oral dose of 25 mg should be considered in those patients (see DOSAGE AND ADMINISTRATION ).PharmacodynamicsEffects of VIAGRA on Erectile ResponseIn 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(R)), after VIAGRA administration compared with placebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post dose. The erectile response, as assessed by RigiScan(R), 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 hours but the response was diminished compared to hours.Effects of VIAGRA on Blood PressureSingle 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 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, 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 ). Figure 2: Mean Change from Baseline in SittingSystolic Blood Pressure, Healthy Volunteers.. Effects of VIAGRA on Cardiac ParametersSingle 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 VIAGRA on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. total dose of 40 mg sildenafil was administered by four intravenous infusions.The results from this pilot study are shown in Table 1; 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 to times higher than the mean maximum plasma concentrations following single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.TABLE 1. HEMODYNAMIC DATA IN PATIENTS WITH STABLE ISCHEMIC HEART DISEASE AFTER IV ADMINISTRATION OF 40 MG SILDENAFILMeans +- SDAt restAfter minutes of exercisenBaseline(B2)nSildenafil(D1)nBaselinenSildenafilPAOP (mmHg)88.1 +- 5.186.5 +- 4.3836.0 +- 13.7827.8 +- 15.3Mean PAP (mmHg)816.7 +- 4812.1 +- 3.9839.4 +- 12.9831.7 +- 13.2Mean RAP (mmHg)75.7 +- 3.784.1 +- 3.7----Systolic SAP (mmHg)8150.4 +- 12.48140.6 +- 16.58199.5 +- 37.48187.8 +- 30.0Diastolic SAP (mmHg)873.6 +- 7.8865.9 +- 10884.6 +- 9.7879.5 +- 9.4Cardiac output (L/min)85.6 +- 0.985.2 +- 1.1811.5 +- 2.4810.2 +- 3.5Heart rate (bpm)867 +- 11.1866.9 +- 128101.9 +- 11.6899.0 +- 20.4In double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to single dose of placebo or VIAGRA 100 mg 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 VIAGRA on the primary endpoint was statistically non-inferior to placebo.Effects of VIAGRA on VisionAt 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 twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry.. image of figure (Mean Sildenafil Plasma Concentrations). image of figure (Mean Change from Baseline).

INFORMATION FOR PATIENTS SECTION.

PATIENT SUMMARY OF INFORMATION ABOUT. This summary contains important information about VIAGRA(R). It is not meant to take the place of your doctors instructions. Read this information carefully before you start taking VIAGRA. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about VIAGRA.This medicine can help many men when it is used as prescribed by their doctors. However, VIAGRA is not for everyone. It is intended for use only by men who have condition called erectile dysfunction. VIAGRA must never be used by men who are taking medicines that contain nitrates of any kind, at any time. This includes nitroglycerin. If you take VIAGRA with any nitrate medicine your blood pressure could suddenly drop to an unsafe or life threatening level. WHAT IS VIAGRAVIAGRA is pill used to treat erectile dysfunction (impotence) in men. It can help many men who have erectile dysfunction get and keep an erection when they become sexually excited (stimulated).You will not get an erection just by taking this medicine. VIAGRA helps man with erectile dysfunction get an erection only when he is sexually excited.o HOW SEX AFFECTS THE BODYWhen man is sexually excited, the penis rapidly fills with more blood than usual. The penis then expands and hardens. This is called an erection. After the man is done having sex, this extra blood flows out of the penis back into the body. The erection goes away. If an erection lasts for long time (more than hours), it can permanently damage your penis. You should call doctor immediately if you ever have prolonged erection that lasts more than hours.Some conditions and medicines interfere with this natural erection process. The penis cannot fill with enough blood. The man cannot have an erection. This is called erectile dysfunction if it becomes frequent problem.During sex, your heart works harder. Therefore sexual activity may not be advisable for people who have heart problems. Before you start any treatment for erectile dysfunction, ask your doctor if your heart is healthy enough to handle the extra strain of having sex. If you have chest pains, dizziness or nausea during sex, stop having sex and immediately tell your doctor you have had this problem. HOW VIAGRA WORKSVIAGRA enables many men with erectile dysfunction to respond to sexual stimulation. When man is sexually excited, VIAGRA helps the penis fill with enough blood to cause an erection. After sex is over, the erection goes away. VIAGRA IS NOT FOR EVERYONEAs noted above (How Sex Affects the Body), ask your doctor if your heart is healthy enough for sexual activity.If you take any medicines that contain nitrates either regularly or as needed you should never take VIAGRA. If you take VIAGRA with any nitrate medicine or recreational drug containing nitrates, your blood pressure could suddenly drop to an unsafe level. You could get dizzy, faint, or even have heart attack or stroke. Nitrates are found in many prescription medicines that are used to treat angina (chest pain due to heart disease) such as:nitroglycerin (sprays, ointments, skin patches or pastes, and tablets that are swallowed or dissolved in the mouth) isosorbide mononitrate and isosorbide dinitrate (tablets that are swallowed, chewed, or dissolved in the mouth) Nitrates are also found in recreational drugs such as amyl nitrate or nitrite (poppers). If you are not sure if any of your medicines contain nitrates, or if you do not understand what nitrates are, ask your doctor or pharmacist.VIAGRA is only for patients with erectile dysfunction. VIAGRA is not for newborns, children, or women. Do not let anyone else take your VIAGRA. VIAGRA must be used only under doctors supervision.o WHAT VIAGRA DOES NOT DOVIAGRA does not cure erectile dysfunction. It is treatment for erectile dysfunction. VIAGRA does not protect you or your partner from getting sexually transmitted diseases, including HIV--the virus that causes AIDS. VIAGRA is not hormone or an aphrodisiac. WHAT TO TELL YOUR DOCTOR BEFORE YOU BEGIN VIAGRAOnly your doctor can decide if VIAGRA is right for you. VIAGRA can cause mild, temporary lowering of your blood pressure. You will need to have thorough medical exam to diagnose your erectile dysfunction and to find out if you can safely take VIAGRA alone or with your other medicines. Your doctor should determine if your heart is healthy enough to handle the extra strain of having sex.Be sure to tell your doctor if you:have ever had any heart problems (e.g., angina, chest pain, heart failure, irregular heart beats, heart attack or narrowing of the aortic valve) have ever had stroke have low or high blood pressure have ever had severe vision loss have rare inherited eye disease called retinitis pigmentosa have ever had any kidney problems have ever had any liver problems have ever had any blood problems, including sickle cell anemia or leukemia are allergic to sildenafil or any of the other ingredients of VIAGRA tablets have deformed penis, Peyronies disease, or ever had an erection that lasted more than hours have stomach ulcers or any types of bleeding problems are taking any other medicines VIAGRA AND OTHER MEDICINESSome medicines can change the way VIAGRA works. Tell your doctor about any medicines you are taking. Do not start or stop taking any medicines before checking with your doctor or pharmacist. This includes prescription and nonprescription medicines or remedies: Remember, VIAGRA should never be used with medicines that contain nitrates (see VIAGRA Is Not for Everyone). If you are taking medicines called alpha-blockers for the treatment of high blood pressure or prostate problems, your blood pressure could suddenly drop. You could get dizzy or faint. If you are taking protease inhibitor, your dose may be adjusted (please see Finding the Right Dose for You). VIAGRA should not be used with any other medical treatments that cause erections. These treatments include pills, medicines that are injected or inserted into the penis, implants or vacuum pumps. VIAGRA contains sildenafil, which is the same medicine found in another drug called REVATIO. REVATIO is used to treat rare disease called pulmonary arterial hypertension. VIAGRA should not be used with REVATIO. FINDING THE RIGHT DOSE FOR YOUVIAGRA comes in different doses (25 mg, 50 mg and 100 mg). If you do not get the results you expect, talk with your doctor. You and your doctor can determine the dose that works best for you.Do not take more VIAGRA than your doctor prescribes. If you think you need larger dose of VIAGRA, check with your doctor. VIAGRA should not be taken more than once day. Your doctor may prescribe lower dose of VIAGRA in certain circumstances. For example:If you are older than age 65, or have serious liver or kidney problems, your doctor may start you at the lowest dose (25 mg) of VIAGRA. If you are taking protease inhibitors, such as for the treatment of HIV, your doctor may recommend 25 mg dose and may limit you to maximum single dose of 25 mg of VIAGRA in 48 hour period. If you have prostate problems or high blood pressure for which you take medicines called alpha blockers, your doctor may start you on lower dose of VIAGRA. HOW TO TAKE VIAGRATake VIAGRA about one hour before you plan to have sex. Beginning in about 30 minutes and for up to hours, VIAGRA can help you get an erection if you are sexually excited. If you take VIAGRA after high-fat meal (such as cheeseburger and french fries), the medicine may take little longer to start working. VIAGRA can help you get an erection when you are sexually excited. You will not get an erection just by taking the pill.o POSSIBLE SIDE EFFECTSLike all medicines, VIAGRA can cause some side effects. These effects are usually mild to moderate and usually dont last longer than few hours. Some of these side effects are more likely to occur with higher doses. The most common side effects of VIAGRA are headache, flushing of the face, and upset stomach. Less common side effects that may occur are temporary changes in color vision (such as trouble telling the difference between blue and green objects or having blue color tinge to them), eyes being more sensitive to light, or blurred vision. In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including VIAGRA) reported sudden decrease or loss of vision in one or both eyes. It is not possible to determine whether these events are related directly to these medicines, to other factors such as high blood pressure or diabetes, or to combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including VIAGRA, and call doctor right away. In rare instances, men have reported an erection that lasts many hours. You should call doctor immediately if you ever have an erection that lasts more than hours. If not treated right away, permanent damage to your penis could occur (see How Sex Affects the Body). Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely reported in people taking PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to other factors, or to combination of factors. If you experience these symptoms, stop taking VIAGRA and contact doctor right away.Heart attack, stroke, irregular heart beats, and death have been reported rarely in men taking VIAGRA. Most, but not all, of these men had heart problems before taking this medicine. It is not possible to determine whether these events were directly related to VIAGRA.VIAGRA may cause other side effects besides those listed on this sheet. If you want more information or develop any side effects or symptoms you are concerned about, call your doctor.o ACCIDENTAL OVERDOSEIn case of accidental overdose, call your doctor right away.o STORING VIAGRAKeep VIAGRA out of the reach of children. Keep VIAGRA in its original container. Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].o FOR MORE INFORMATION ON VIAGRAVIAGRA is prescription medicine used to treat erectile dysfunction. Only your doctor can decide if it is right for you. This sheet is only summary. If you have any questions or want more information about VIAGRA, talk with your doctor or pharmacist, visit www.viagra.com, or call 1-888-4VIAGRA.LAB-0220-7.0 January 2010 Repackaged by;Rebel Distributors CorpThousand Oaks, CA 91320 nitroglycerin (sprays, ointments, skin patches or pastes, and tablets that are swallowed or dissolved in the mouth) isosorbide mononitrate and isosorbide dinitrate (tablets that are swallowed, chewed, or dissolved in the mouth) VIAGRA does not cure erectile dysfunction. It is treatment for erectile dysfunction. VIAGRA does not protect you or your partner from getting sexually transmitted diseases, including HIV--the virus that causes AIDS. VIAGRA is not hormone or an aphrodisiac. have ever had any heart problems (e.g., angina, chest pain, heart failure, irregular heart beats, heart attack or narrowing of the aortic valve) have ever had stroke have low or high blood pressure have ever had severe vision loss have rare inherited eye disease called retinitis pigmentosa have ever had any kidney problems have ever had any liver problems have ever had any blood problems, including sickle cell anemia or leukemia are allergic to sildenafil or any of the other ingredients of VIAGRA tablets have deformed penis, Peyronies disease, or ever had an erection that lasted more than hours have stomach ulcers or any types of bleeding problems are taking any other medicines Remember, VIAGRA should never be used with medicines that contain nitrates (see VIAGRA Is Not for Everyone). If you are taking medicines called alpha-blockers for the treatment of high blood pressure or prostate problems, your blood pressure could suddenly drop. You could get dizzy or faint. If you are taking protease inhibitor, your dose may be adjusted (please see Finding the Right Dose for You). VIAGRA should not be used with any other medical treatments that cause erections. These treatments include pills, medicines that are injected or inserted into the penis, implants or vacuum pumps. VIAGRA contains sildenafil, which is the same medicine found in another drug called REVATIO. REVATIO is used to treat rare disease called pulmonary arterial hypertension. VIAGRA should not be used with REVATIO. Do not take more VIAGRA than your doctor prescribes. If you think you need larger dose of VIAGRA, check with your doctor. VIAGRA should not be taken more than once day. If you are older than age 65, or have serious liver or kidney problems, your doctor may start you at the lowest dose (25 mg) of VIAGRA. If you are taking protease inhibitors, such as for the treatment of HIV, your doctor may recommend 25 mg dose and may limit you to maximum single dose of 25 mg of VIAGRA in 48 hour period. If you have prostate problems or high blood pressure for which you take medicines called alpha blockers, your doctor may start you on lower dose of VIAGRA. image of word Viagra. image of Pfizer logo.