EFTA00625099.pdf

VIAGRA® (sildenafil citrate) Tablets DESCRIPTION VIAGRA° , 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-methy1-7-oxo-3-propy1-1H- pyrazolo[4,3-d]pyrimidin-5-y1)-4-ethoxyphenylisulfony1J-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. CLINICAL PHARMACOLOGY Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavemosum 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 cavemosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavemosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDES), which is responsible for degradation of cGMP in the corpus cavemosum. When sexual stimulation causes local release of NO, inhibition of PDES by sildenafil causes increased levels of cGMP in the corpus cavemosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavemosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. 1 EFTA00625099 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, PDE1 0, 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 cavemosum 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 Metabolism VIAGRA is rapidly absorbed after oral administration, with a 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 4 hours. Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below: Figure 1: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers. 2 EFTA00625100 Absorption and Distribution: 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 60 minutes and a mean reduction in C. 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 Excretion: 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 PDES 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. Pharmacokinetics in Special Populations Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy 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 Insufficiency: In volunteers with mild (CLcr=50-80 mUmin) and moderate (CLcr=30-49 mUmin) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr=c30 mUmin) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C. 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 Insufficiency: In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C. (47%) compared to 3 EFTA00625101 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 >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 DOSAGE AND ADMINISTRATION). Pharmacodynamics Effects of VIAGRA on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan®), after 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. Effects of VIAGRA on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of 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). 4 EFTA00625102  / - 15 -25 24 Figure 2: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers. Effects of VIAGRA on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of VIAGRA on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Gain 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. 5 EFTA00625103 TABLE 1. HEMODYNAMIC DATA IN PATIENTS WITH STABLE ISCHEMIC HEART DISEASE AFTER IV ADMINISTRATION OF 40 MG SILDENAFIL Means ± SD At rest After 4 minutes of exercise n Baseline n Sildenafil n Baseline n Sildenafil (B2) (DI) PAOP (mmHg) 8 8.1 ± 5.1 8 6.5 ± 4.3 8 36.0 ± 13.7 8 27.8 ± 15.3 Mean PAP (mmHg) 8 163 ± 4 8 12.1 ± 3.9 8 39.4 ± 12.9 8 31.7 ± 13.2 Mean RAP (mmHg) 7 5.7 ± 3.7 8 4.1 ± 33 - - - - Systolic SAP (mmHg) 8 150.4 ± 12.4 8 140.6 ± 16.5 8 199.5 ± 37.4 8 187.8 ± 30.0 Diastolic SAP (mmHg) 8 73.6 ± 7.8 8 65.9 ± 10 8 84.6 ± 9.7 8 79.5 ± 9.4 Cardiac output (L/min) 8 5.6 ± 0.9 8 5.2 ± 1.1 8 11.5 ± 2.4 8 10.2 ± 3.5 Heart rate (bpm) 8 67 ± 11.1 8 66.9 ± 12 8 101.9 ± 11.6 8 99.0 ± 20.4 In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or 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. Effects of VIAGRA on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry. Clinical Studies 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; 6 EFTA00625104 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. 7 EFTA00625105  Effect of VIAGRA on Maintenance of Erection by Baseline Score 80 70 • O0 60 • M1 Fp 50 M2 CI M 40 • O3 M4 O5 "e3 20 aE 10 1 2 3 4 5 Baseline score Effect of Placebo on Maintenance of Erection by Baseline Score 80 70 • O0 1 60 • • 1 (7) 50 • I E2 • 40 O3 S 30 • E4 M5 `6 20 • • 10 • 0i 0 1 2 3 4 Baseline score Figure 3. Effect of VIAGRA and Placebo on Maintenance ofErection 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% 8 EFTA00625106 on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar. a 100 82% E 80 a C g 60 2 40 3 aC 24% co ca 20 C C 0. 0 Placebo VIAGRA VIAGRA VIAGRA n=463 25 mg 50 mg 00 mg n=214 n=391 n=380 Treatment group Overall treatment p<0.000I 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 (I 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 9 EFTA00625107 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 (TURF) 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. INDICATION AND USAGE VIAGRA is indicated for the treatment of erectile dysfunction. 10 EFTA00625108  CONTRAINDICATIONS Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY), 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 CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism). In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mUmin), 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. WARNINGS 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 CLINICAL PHARMACOLOGY: Pharmacodynamics). 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. II EFTA00625109 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 resting hypotension (BP <90/50) or hypertension (BP >170/110); • Patients with cardiac failure or coronary artery disease causing unstable angina; • Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); • Patients with sickle cell or related anemias. 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 Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). PRECAUTIONS General 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 Drug Interactions) leading to symptomatic hypotension (e.g. dizziness, lightheadedness, fainting). 12 EFTA00625110 Consideration should be given to the following: - 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 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, cavemosal 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. Information for Patients 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 13 EFTA00625111 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 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 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. 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 Interactions Effects of Other Drugs on VIAGRA In vitro studies: Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes 14 EFTA00625112 may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. In vivo studies: 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 DOSAGE AND ADMINISTRATION). 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 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 a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg M.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg M.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cm.. 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 15 EFTA00625113 nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence. Effects of VIAGRA on Other Drugs In vitro studies: 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. In vivo studies: 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: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg Supine 7.4 (-0.9, 15.7) Standing 6.0 (-0.8, 12.8) 2 3 4 B B floe Postdoim Carl Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline 16 EFTA00625114 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: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI) Supine 9.08 (5.48, 12.68) Standing 11.62 (7.34, 15.90) 17 EFTA00625115  40 30 20 10 0 • • -10 -40 •+• Dosato412 • 71anobn e - O- PDonaz441n • 411043•211 50 ng -50 0.000 1.410 2.000 3.000 4.400 5.000 6.040 7.419 4.000 TI Pnratice• Ihr) 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 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 I, 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 I. 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). 18 EFTA00625116 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 mg Supine 7.9 (4.6, 11.1) Standi