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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 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 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. Viagra (sildenafil citrate) is formulated as blue, film-coated rounded-diamond-shaped 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, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake. 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 has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (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 ). 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. Viagra is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. 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 ). Both sildenafil and the metabolite have terminal half lives of about 4 hours. in Healthy Male Volunteers. Viagra 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 a high fat meal, the rate of absorption is reduced, with a mean delay in T 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. Sildenafil 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 a 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 sildenafil's 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 a 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 a population pharmacokinetic approach. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18–45 years). In volunteers with mild (CLcr=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of Viagra (50 mg) were not altered. In volunteers with severe (CLcr=<30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C compared to age-matched volunteers with no renal impairment. In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C (47%) compared to age-matched volunteers with no hepatic impairment. Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients (see ). 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 Viagra administration compared with placebo. Most studies assessed the efficacy of Viagra 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. 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 8.4/5.5 mmHg). The decrease in 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 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 ). Systolic Blood Pressure, Healthy Volunteers. 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 Viagra 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 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 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. 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 Viagra 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 Viagra on the primary endpoint was statistically non-inferior to placebo. 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 twice the maximum recommended dose revealed no effects of Viagra on visual acuity, intraocular pressure, or pupillometry. In clinical studies, Viagra was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. Viagra was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Viagra was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Viagra demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. The effectiveness of Viagra was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered. The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 3, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 3 shows that regardless of the baseline levels of function, subsequent function in patients treated with Viagra was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline. Figure 3. Effect of Viagra and Placebo on Maintenance of Erection by Baseline Score. The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 4. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of Viagra, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar. Figure 4. Percentage of Patients Reporting an Improvement in Erections. The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period. In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of Viagra on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50–100 mg of Viagra vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on Viagra vs about 20% on placebo. During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that Viagra improved their erections. Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. Viagra improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction. One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of Viagra; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on Viagra compared to placebo. On a global improvement question, 57% of Viagra patients reported improved erections versus 10% on placebo. Diary data indicated that on Viagra, 48% of intercourse attempts were successful versus 12% on placebo. One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of Viagra. On a global improvement question, 83% of patients reported improved erections on Viagra versus 12% on placebo. Diary data indicated that on Viagra, 59% of attempts at sexual intercourse were successful compared to 13% on placebo. Across all trials, Viagra improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo. Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of Viagra patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of Viagra. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for Viagra and 29% for placebo. A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. Viagra was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and antihypertensives/diuretics. Analysis of the safety database showed no apparent difference in the side effect profile in patients taking Viagra with and without antihypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions. Viagra is indicated for the treatment of erectile dysfunction. ), Viagra was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated. After patients have taken Viagra, it is unknown when nitrates, if necessary, can be safely 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) (see ). In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin), 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 coadministered at this time point. Viagra is contraindicated in patients with a known hypersensitivity to any component of the tablet. There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including Viagra, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. Viagra has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), (see ). While this normally would be expected to be of little consequence in most patients, prior to prescribing Viagra, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Patients with the following underlying conditions can be particularly sensitive to the actions of vasodilators including Viagra – those with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure. There is no controlled clinical data on the safety or efficacy of Viagra in the following groups; if prescribed, this should be done with caution. Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases). Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Viagra. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If Viagra is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Visual disturbances occurred more commonly at higher levels of sildenafil exposure. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200–800 mg). To decrease the chance of adverse events in patients taking ritonavir, a decrease in sildenafil dosage is recommended (see , ). The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment. Before prescribing Viagra, it is important to note the following: Caution is advised when Phosphodiesterase Type 5 (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 ) leading to symptomatic hypotension (e.g. dizziness, lightheadedness, fainting). Patients should be stable on alpha-blocker therapy prior to initiating a 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 a 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 a 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 a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and Viagra, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted (see ). 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 Peyronie's 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. Physicians 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 a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a 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 ). 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 , ). Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Viagra. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. 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. Sildenafil 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. Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when coadministered with Viagra (50 mg) to healthy volunteers. When a single 100 mg dose of Viagra was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single dose) resulted in a 140% increase in sildenafil C and a 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 a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) (see ). In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Viagra (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C and a 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 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Viagra had no effect on ritonavir pharmacokinetics (see ). Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. In a 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 a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C . 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. Sildenafil is a weak inhibitor of the cytochrome P450 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 Viagra will alter the clearance of substrates of these isoenzymes. Three 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, a single oral dose of Viagra 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, Viagra 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 Viagra dose was reduced to 25 mg. Thereafter, 17 subjects were treated with Viagra 25 mg or matching placebo in combination with doxazosin 4 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: 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 Viagra 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 Viagra 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following Viagra 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 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, a 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 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. In the second study, a single oral dose of Viagra 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, Viagra 50mg 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 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, a 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: 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 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 Viagra 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30mmHg following Viagra 50 mg and one subject with a decrease from baseline in standing systolic BP > 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, a single oral dose of Viagra 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 Viagra 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 Viagra 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, Viagra 100mg 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 Viagra 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 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: 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 a standing SBP of < 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 a decrease from baseline in standing systolic BP >30mmHg following Viagra 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 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, 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. 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 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 at steady state (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C of bosentan (125 mg b.i.d.). Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for 24 months at a 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 a mg/m 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, a 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 Use Viagra is not indicated for use in newborns, children, or women. No 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 a mg/m basis in a 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. ). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered (see ). Viagra was administered to over 3700 patients (aged 19–87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse events for Viagra (2.5%) was not significantly different from placebo (2.3%). The adverse events were generally transient and mild to moderate in nature. In trials of all designs, adverse events reported by patients receiving Viagra were generally similar. In fixed-dose studies, the incidence of some adverse events increased with dose. The nature of the adverse events in flexible-dose studies, which more closely reflect the recommended dosage regimen, was similar to that for fixed-dose studies. When Viagra was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials, the following adverse events were reported: Other adverse reactions occurred at a rate of >2%, but equally common on placebo: respiratory tract infection, back pain, flu syndrome, and arthralgia. In fixed-dose studies, dyspepsia (17%) and abnormal vision (11%) were more common at 100 mg than at lower doses. At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently. The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to Viagra is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful: Body as a whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury. Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy. Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia. Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis. Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia. Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased. Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis. Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes. Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia. Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of Viagra. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Viagra without sexual activity. Others were reported to have occurred hours to days after the use of Viagra and sexual activity. It is not possible to determine whether these events are related directly to Viagra, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors (see for further important cardiovascular information). Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including Viagra. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of Viagra, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors (see ). Nervous: seizure and anxiety. Urogenital: prolonged erection, priapism (see ), and hematuria. Special Senses: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease or bleeding, vitreous detachment/traction, paramacular edema and epistaxis. Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including Viagra. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors (see ). In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates 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. For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, Viagra may be taken anywhere from 4 hours to 0.5 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day. The following factors are associated with increased plasma levels of sildenafil: age >65 (40% increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renal impairment (creatinine clearance <30 mL/min, 100%), and concomitant use of potent cytochrome P450 3A4 inhibitors [ketoconazole, itraconazole, erythromycin (182%), saquinavir (210%)]. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients. Ritonavir greatly increased the systemic level of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC, see .) Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg of Viagra in a 48 hour period. Viagra was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated. When Viagra is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating Viagra treatment and Viagra should be initiated at the lowest dose (see ). Viagra (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. LAB-0221-8.0 ®. It is not meant to take the place of your doctor's 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 a 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 Viagra? Viagra is a 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 a man with erectile dysfunction get an erection only when he is sexually excited. When a 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 a long time (more than 6 hours), it can permanently damage your penis. You should call a doctor immediately if you ever have a prolonged erection that lasts more than 4 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 a 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. Viagra enables many men with erectile dysfunction to respond to sexual stimulation. When a man is sexually excited, Viagra helps the penis fill with enough blood to cause an erection. After sex is over, the erection goes away. As 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 a 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 a doctor's supervision. Viagra does not cure erectile dysfunction. It is a 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 a hormone or an aphrodisiac. Only 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 a 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. 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 any blood problems, including sickle cell anemia or leukemia have a deformed penis, Peyronie's disease, or ever had an erection that lasted more than 4 hours Some 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 a 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 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 a larger dose of Viagra, check with your doctor. Viagra should not be taken more than once a day. Your doctor may prescribe a 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 a 25 mg dose and may limit you to a maximum single dose of 25 mg of Viagra in a 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 a lower dose of Viagra. Take Viagra about one hour before you plan to have sex. Beginning in about 30 minutes and for up to 4 hours, Viagra can help you get an erection if you are sexually excited. If you take Viagra after a high-fat meal (such as a cheeseburger and french fries), the medicine may take a 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. Like all medicines, Viagra can cause some side effects. These effects are usually mild to moderate and usually don't last longer than a 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 a 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 a 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 a combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including Viagra, and call a doctor right away. In rare instances, men have reported an erection that lasts many hours. You should call a doctor immediately if you ever have an erection that lasts more than 4 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 a combination of factors. If you experience these symptoms, stop taking Viagra and contact a 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. In case of accidental overdose, call your doctor right away. Keep Viagra out of the reach of children. Keep Viagra in its original container. Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Viagra is a prescription medicine used to treat erectile dysfunction. Only your doctor can decide if it is right for you. This sheet is only a 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-0220-6.0 free viagra sample As effective than the normal, if not better. Non-prescription drug, buy generic viagra over the Internet. Although generic viagra is not an FDA approved drug, it is manufactured by Ajanta Pharma in India a reputable pharmacy company who has being making popular generic drugs since 1990. One thing to do before buying generic viagra over the Internet, is to check phone numbers and contact details on the suppliers website. If something looks fishy, don’t even go there! Click here to on our website today for an excellent experience!The latest alert was prompted by a case report in the journal of laryngology & otology of sudden hearing loss in a man taking viagra. a search of fda records found 29 similar reports involving ed drug users and a few people who took the drugs during clinical trials. although hearing loss is common in men in their 50s -- the age group most likely to take ed drugs -- age-related loss tends to be gradual, unlike the kind tied to the warning. the fda has also issued a hearing-loss warning on revatio, a blood pressure drug in the same class. revatio users who experience hearing problems should stay on the drug until they have checked with their doctor. ed drugs, on the market for more than a decade, generally have an excellent safety record. more-common problems include flushing and muscle soreness. Treat Sexual Dysfunctions with Aromatherapy Sexual issues such as impotence, infertility and frigidity are related to a psychological problem that has established itself from stress-related conditions. Generally, the loss of physical sexual function can lead to its own set of emotional feedback and can give rise to stress, depression and anxiety. Libido problems like frigidity (anorgasmia), impotence and retarded ejaculation can arise because of emotional frustration or negative feelings, resulting in a loss in sexual appetite. When the emotional problems have come to an end, the libido and function will return. In cases of frigidity and retarded ejaculation, longer time spent in foreplay and different sexual positions may play a prominent role in solving the problem. In this regard, vaginismus, which is the involuntary spasm of the vaginal muscles is, in theory, attached to overwhelming feelings of fear arising due to trauma or a violent sexual experience. In a few cases vaginismus can be a result of lack of sexual experience, which may lead to fear of sexual intercourse. All sexual issues can result in infertility as conception is less likely to arise if there is an issue with one or both partners’ sexual function. Stress can have a significant bearing on the menstrual cycle, leading to conditions like amenorrhea, dysmenorrhea and menorrhagia affecting a woman’s ability to conceive. In virtually all cases of sexual dysfunction, there is the urgent requirement of a supportive, sympathetic, cooperative partner in the relationship. Establishing intimacy and trust is also essential. Aromatherapy can play a prominent role when used in aromatic baths or massage, which can be termed as intimate routines. In addition, aromatic bathing and massage can assist in keeping you relax and open the method for sexual feedback between two individuals. Massage can turn out to be a sensual experience and a part of foreplay. Another significant factor when dealing with a sexual issue, is the body’s energy system. The chakra attached to sexuality is the sacral chakra, situated between the genitals and the naval. Blockages in this chakra can manifest as psycho-sexual ills. The sacral chakra is orientated to your self gratification, physical comfort, satisfaction and sexuality. With the help of the sacral chakra, you can regulate your feelings as well as emotional expressions. Furthermore, the gonads are situated within the sacral chakra. The sacral chakra can be defined as the sphere of desires, physical pleasures and happiness; it is also the home of the five senses. You are attached to feelings and sense of physical balance with the assistance of this chakra. viagra attorneys However discomfiting the commercials, the -- on March 27, 1998 -- is a landmark day in the history of sex. It seemed at the time like a biomedical revolution was upon us all, and about five minutes after word of the magical med went global, the question first was asked: Where is the women's version of Viagra? The short answer: They're still working on it. A bunch of companies have tried and failed to create "pink Viagra," as it's often called. Other companies have drugs in late stages of clinical testing, including a gel that recently began a make-or-break nationwide study with several thousand women. Give us five years, maybe less, say the most optimistic researchers and doctors. Though it's unclear exactly how many women would ask for a prescription, no one doubts that the first company that gets to market a remedy for female sexual dysfunction, as it's formally known, will earn a fortune. But as this race reaches what could be its final lap, not all of the spectators are cheering. Some, in fact, are booing as loudly as they can. A modest-size but fervent group of psychologists, academics and public health advocates contend that FSD isn't an authentic medical condition, or at least not the sort of problem that should be treated with drugs. These aren't the obtuse male physicians who for decades have been telling women distressed by their lack of libido that "it's all in your head." The anti-FSD crowd is mostly women, many of them self-described feminists. The most prominent is Leonore Tiefer, a psychotherapist and clinical associate professor at , who has long decried what she calls "the medicalization of women's sexuality." "Drug companies want to say to women, 'You don't need to know anything; you can have the satisfying sex life that you seek -- people dancing on TV, the whole bit -- without knowing anything. Just ask your doctor,' " she says. "I resent that, because there are specific harms that come from being ignorant and dependent in the world we live in. There may be lots of people who aren't interested in sex, but is there a medical reason for that, and do we diagnose that?" Tiefer's critique centers, in part, on the way that pink Viagra is sure to be marketed -- with ads day and night, suggesting that women who aren't feeling frisky have a medical problem. She and her allies -- organized as the New View Campaign -- are also galled that so much money and media attention are heaped on the lust drug, even before it exists, when for many women the solution to their libido problems isn't that exotic. Maybe they have a partner who hasn't a clue about technique.Maybe they're stressed out. Maybe they can't possibly get in the mood because they're so busy raising children. Therapy, counseling, even free day care, says the New View Campaign, might do more for women's sex lives than any drug company ever could. "People walk out of their doctors' offices with a prescription in hand 85 percent of the time," says Meika Loe, the author of "The Rise of Viagra" and a New View endorser. "But health insurers won't pay if you want to talk to a counselor or if you need advice about how to communicate your sexual desires. We've got a health-care system that is almost entirely focused on medical solutions." On the other side of the FSD divide, allied with the pharmaceutical companies, is a group of physicians who are prescribing off-label treatments for women vexed by their sex lives. (Off-label means the drug hasn't been approved by the FDA for that specific treatment.) The highest-profile of the bunch is Irwin Goldstein, the director of sexual medicine at San Diego's Alvarado Hospital. He and Tiefer have debated the topic of FSD for a decade, but as far as he's concerned, there's really nothing to discuss. He's been using hormones to treat women, and he'll happily put you in touch with patients who will rhapsodize about the results. Women like Virginia, a 60-year-old native of and an artist who, for privacy reasons, asked that her last name be omitted. She'd spent years asking doctors for medical help to boost her sex drive, which had once been voracious. All of them, she says, "rolled their eyes and harrumphed and tried to change the subject." "But when I was younger, a really strong libido was just part of who I was," she goes on. "Losing that was like losing a good friend." Three years ago, she heard Goldstein interviewed on . Within weeks she flew to , the site of his practice at the time, and she soon was taking several hormones. There was tinkering with the combination and the dosage, but a few weeks later she suddenly felt "perky" -- more confident about herself as a sexual being and more attractive. She also started having better sex. generic viagra online drugs What is Viagra used for? Viagra is used to treat impotence in men. Viagra increases the body’s ability to achieve and maintain an erection during sexual stimulation. Viagra does not protect you from getting sexually transmitted diseases, including HIV. take Viagra? Men who are currently using medicines that contain nitrates, such as nitroglycerin should not use Viagra because taken together they can lower the blood pressure too much. Viagra should not be used by women or children. In patients taking Viagra, several heart-related side effects have been reported, including heart attack, sudden death, irregular heart rhythm, stroke, chest pain, and increased blood pressure. It is not possible to determine whether these events are directly related to Viagra, to sexual activity, to the patient’s heart condition, to a combination of these factors, or to other factors. taking certain medications at the same time (e.g., ketoconazole, itraconazole, erythromycin and saquinavir). In these patients, the recommended starting dose of Viagra is 25 mg. Heart attack, stroke, or life-threatening irregular heart rhythm within the last 6 months Because Viagra lowers blood pressure, your doctor will evaluate your overall medical condition to determine if Viagra, in combination with sexual activity, could adversely affect you. Viagra can cause a rare but serious condition of prolonged erection (priapism). It is important to contact your health care provider immediately if your erection lasts longer than 4 hours. Men for whom sexual activity is inadvisable may not be good candidates for Viagra. Tell your doctor if you are taking protease inhibitors for the treatment of HIV. You should have a complete medical history and exam to determine the cause of your impotence before taking Viagra. Men who have medical conditions that may cause a sustained erection such as sickle cell anemia, leukemia or multiple myeloma or who have an abnormally shaped penis may not be able to take Viagra. There are several medications that are known to interact with Viagra, so be sure to tell your doctor about all medications you are taking including those you can get without a prescription. Viagra has not been studied with other treatments for impotence, so use in combination with other treatments is not recommended. What are some possible side effects of Viagra? a complete list of side effects reported with Viagra. Your health care provider can discuss with you a more complete list of side effects.) ). The following is a listing of the most common side effects Visual changes such as mild and temporary changes in blue/green colors or increased sensitivity to light. For more detailed information about Viagra, ask your health care provider. Drugs for treating Erectile Dysfunction (ED) can be taken orally, injected directly into the penis or inserted into the urethra at the tip of the penis. Viagra was the first pill to treat ED when the Food and Drug Administration (FDA) approved it in 1998. Later, vardenafil hydrochloride (Levitra) and tadalafil (Cialis) were given the green light by the FDA to treat ED. Many other oral medicines are being tested for safety and effectiveness. Viagra, Levitra and Cialis belong to a class of drugs known as phosphodiesterase (PDE) inhibitors. The medication is generally taken an hour before any intended sex act, these drugs work by increasing the effects of nitric oxide. Nitric oxide is a chemical whose main function is to relax the smooth muscles in the penis during sexual stimulation and allow increased blood flow. While there is no doubt that oral medicines improve the response to sexual stimulation, they do not trigger an automatic erection (as injections do). The advisable dose for Viagra is about 50 mg, though the physician may adjust this dose to a range of 25 to 100 mg depending on the patient. The advisable dose for Levitra or Cialis is about 10 mg, which can be increased to 20 mg if 10 mg turns out to be insufficient. A decreased dose of 5 mg (or as low as 2.25 mg) is available on the market for patients who take other medicines or have diseases that may decrease in the body's ability to use the drug. No PDE inhibitors should be used more than once a day. It is mandatory that men who take nitrate-based drugs, such as nitro-glycerine for heart issues, should not use either drug because the combination can lead to a sudden decrease in blood pressure. In addition, it is recommended that you tell your doctor if you take any drugs known as alpha-blockers. These are mainly used to treat prostate enlargement or high blood pressure. Often, oral testosterone can minimize ED in men with low levels of natural testosterone, but it is often ineffective and may lead to liver damage. Many patients are of the opinion that other oral drugs (namely yohimbine hydrochloride, dopamine, serotonin agonists, and trazodone) are pretty effective, but the results of scientific research studies have been inconsistent to say the least. Improvements may be instances of the placebo effect, a change that results from the patient's belief that an improvement will take place. generic viagra risks Male impotence a problem that virtually every man fears, but at sometime or other in life every man has to confront Erectile Dysfunction (ED). A man’s psychology plays a prominent part in his sexual relationship. If he is depressed, stressed or tense, there is bound to be some impact on his sexual relationship. Anxiety about a man’s sexual routine makes him more stressed and causes his ability to perform to decrease. Erectile Dysfunction can be defined as the inability to have or maintain an erection long enough to have satisfactory sexual intercourse. According to research, ED afflicts nearly 30 million men in America alone and is a cause of great tension. The ideal solution to male sexual impotence issues lies in the little blue pill known as Viagra. Viagra has been quite a handy tool to men who have ED or may be suffering from any degree of male sexual dysfunction. Since the advent of Viagra there has been a great deal of confidence in the patients of erectile dysfunction whether suffering because of the physical or psychological issues. Viagra revives the feeling of self-esteem and manliness, which seems to be lost if you are suffering from ED. Viagra works by enhancing the flow of blood in the penile region and causing a firm erection. The sexual lives of many men have improved because they have the option of Viagra. Viagra can proudly claim to be the first anti-impotence oral pill. The basic chemical base in Viagra is sildenafil citrate. This chemical that treats erectile dysfunction by enabling the man to have an erection long enough to satisfactorily complete sexual intercourse. Many people think that Viagra will enhance their libido or improve their sexual prowess, but this is totally baseless. Viagra can surely be termed as a sex pill, but it is not a libido enhancer drug at all. As a matter of fact, Viagra just acts on the chemicals and enzymes present in your body causing an increased flow of blood in the penis to cause an erection.
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You have to be cautious. There are literally thousands of internet operations ready to sell you unregulated versions of Pfizer's Viagra. Often the sites claim to be selling the real thing, and it can be a daunting task to identify a safe resource for genuine, Pfizer Viagra. Ukmedix has had to compete with these fakes (which often are cheaper) and has even had to assist in identifying illegal operations (fakes are a threat to your safety, and ultimately Pfizer). In order to stand out from the crowd and reassure our customers Ukmedix produces useful customer tools e.g. a forum dedicated to viagra and makes sure that with every order sent batch numbers and manufacturer;s hall marks are always maintained. Dispatch pharmacists* are always available on receipt of your order for any further queries of authenticity. This means you can trace the product all the way back to Pfizer's manufacturing facility and even know the date your viagra was produced. *A UK pharmacist will always be able to assist you and any licensed pharmacy should be able to verify the viagra batch number. Apart from being unsafe and more then likely to be completely ineffective, fake viagra (wherever it has been produced) has passed no tests, is unregulated and for all you know may have been produced in a garden shed. In some instances dangerous substances have been found in this copied viagra, which would completely defeat the purpose of your seeking help with impotence in the first place! Ukmedix is obviously a business, but we care about our reputation and we care about our customers. We support Pfizer's Safe Drug Initiative which has been created to specifically find and close any illegal sellers of the unsubstantiated, fake viagra being sold on and offline. To this extent we want to know if you have been sold viagra that you think may be fake or viagra that doesn't look like it should. Contact ukmedix and we will gladly assist you and qualify your findings to Pfizer on your behalf. The fact is that fake viagra could have any substances in it and it is not to be trusted as a suitable replacement for the real thing. Impotence is a health condition that may be complex in its causes. Unnecessary e-mail spam on viagra or ludicrous claims that viagra will fix everything in your life are not what we are about. We never send out unsolicited e-mail and try to encourage you to research as much as you can yourself/ through your doctor and local pharmacists. Viagra has truly revolutionized many millions of lives, but viagra (that is Pfizer's viagra) is not suitable for everybody, and fake viagra is suitable for NO-ONE.When Pfizer released Viagra in 1998, they revolutionized oral medical management for erectile dysfunction. Along with its rival medications Cialis and Levitra, Viagra has become a popular drug of choice against impotence. However, anti - impotence drugs are not just used by older men anymore. A growing number of men under the age of 55 are using the �blockbuster pill'. A study of more than 5 million insured adults in 1998 to 2002 found that the fastest - growing segments of Viagra users were aged 18 to 55. These finding suggest use of Viagra not only as anti - impotence drug but as enhancement or recreational agent. How does anti - impotence pills like Viagra work? These drugs dilate blood vessels in the genital region leading to an increased blood flow and consequently, erection. However, it does very little to libido, sensation and sensuality. The effects of Viagra are noticed after an hour of taking the pill and the ease of erection lasts up to 12 hours. There may be side effects however such as headaches, flushes, nasal congestion or runny nose, malaise, changes in blood pressure, nausea, irregular heartbeats, and chest pain. Furthermore, anti - impotence drugs such as Viagra and Cialis increases the risk of vision loss in impotent men who have a history of hypertension and heart failure. Results of a study conducted by scientists at the University of Alabama in Birmingham showed that men who suffered heart attack were 10 times more likely to have optic nerve damage if they had been taking anti - impotence pills. Dr. Gerald McGwin, the one who headed the study, observed that there is a strong and statistically significant association between the use of Viagra and/or Cialis and non - anteritic anterior ischaemic optic neuropathy (NAION). NAION is the most common cause of acute optic nerve damage for people over 50 years old. It can cause the loss of vision in one or both eyes. There are also other impotent pills in the market which the Food and Drug Administration (FDA) warns the public about. These products, usually available through the internet, illegally contain the same ingredients as the prescription medicines approved by the FDA. Some of the product names listed by FDA are Zimaxx, Libidus, Neophase, Nasutra, Vigor - 25, Actra - Rx, and 4Everon. Tests showed that these products either contain sildenafil, the active ingredient in Viagra, or valdenafil, the active ingredient in Levitra. Dr. Steven Galson, Director of FDA's Center for Drug and Evaluation and Research, warns that these products threaten the public health because they contain undeclared chemicals similar or identical to the ingredients used in prescription medicines approved by the FDA. Furthermore, because you do not have to consult a doctor to buy this, you may not be aware that these ingredients can have dangerous interactions with drugs prescribed for heart disease, and may dangerously lower your blood pressure.
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