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The investigator was provided a sealed copy of the randomisation codes and was instructed to break the treatment code only in the event of an emergency.

Active treatment and corresponding placebo tablets were identical in packaging and appearance. During the DB phase, the primary efficacy variables were responses to questions “When you attempted sexual intercourse, how often were you able to penetrate your partner?” (Q3) and “When you attempted sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?” (Q4) of the 15 item International Index of Erectile Function (IIEF).

The IIEF is a validated questionnaire that has been used for the clinical assessment of ED.

18 Each question of the IIEF is scored on a categorical scale of 1 (“almost never/never”) to 5 (“almost always/always”), with a score of 0 indicating “did not attempt sexual intercourse”. Secondary efficacy variables were responses to three global efficacy questions (GEQs): GEQ1: “Compared to having no treatment at all for your erection problem, has the medication you have been taking over the past 4 weeks improved your erections?” and GEQ2: “If yes, has the improvement in your erections allowed you to engage in satisfactory sexual activity?”.

GEQ3 asked: “When you took a dose of study drug and had sexual stimulation, how often did you get an erection that allowed you to engage in satisfactory sexual activity?”. Additional secondary efficacy measures were analyses of IIEF domains, for example, orgasmic function (Q9: “When you had sexual stimulation or intercourse, how often did you ejaculate?” and Q10: “When you had sexual stimulation or intercourse, how often did you have the feeling of orgasm?”) and sexual desire (Q11: “Over the past 4 weeks, how often have you felt sexual desire?” and Q12: “Over the past 4 weeks, how would you rate your level of sexual desire?”).

The DB end point efficacy assessment served as baseline for the OLE phase. At the final OLE visit, a limited assessment of efficacy was made based on responses to the three GEQs.

The Life Satisfaction Checklist is an eight item general QoL questionnaire, with questions on the patient’s satisfaction with life as a whole, sexual life, partnership relation, family life, social contacts, and leisure, vocational, and financial situations.

19 The Erection Distress Scale is a disease specific instrument with five questions on the patient’s concerns with his erection problems.

These were: “Were you frustrated about your erection problems?”, “Did you feel weighed down by your erection problems?”, “Were you discouraged by your erection problems?”, “Did you feel despair over your erection problems?”, and “Were your erection problems a worry in your life?”. Responses to each question of the Life Satisfaction Checklist and the Erection Distress Scale were scored from 1 (none of the time) to 6 (all of the time).

Calculations were performed to determine the sample size needed to detect a statistical difference in the mean end point response for sildenafil (combined 25, 50, and 100 mg dose groups) versus placebo.

Based upon a difference of 1.33 in mean scores and assuming a common standard deviation for sildenafil and placebo of 2.0, a sample size of 50 patients per treatment arm was sufficient to achieve a power of 90% to detect the specified difference between the two treatment groups using an approximation (two sided, ? = 0.05) to the test comparing two means for normally distributed responses. Assuming an overall drop out rate of 25%, a 1:1 randomisation ratio of sildenafil to placebo, sufficient power to be able to conduct the primary analysis of efficacy, analysis of covariance, including terms for treatment group, centre, baseline value for efficacy variables, and other covariates as required, 250 patients, 125 in each arm, were to be randomised to study drug; in total, 218 patients were randomised. Intent-to-treat analyses were performed on all efficacy and QoL variables, and included all patients with at least one assessment after randomisation who had taken at least one dose of study drug. To be eligible for inclusion in safety analyses, patients must have taken at least one dose of study drug.

Statistical analysis of responses to IIEF Q3 and Q4 and GEQ3 was performed for each question using analysis of covariance. Statistical analysis of responses to GEQ1 and GEQ2 (yes/no) was performed for each question using a logistic regression model.

The mean frequency of responses to each question of the Life Satisfaction Checklist and to the five questions of the Erection Distress Scale for each treatment was calculated and expressed as the least squares mean±standard error (SE).

Each question was fitted with an analysis of covariance model, which included terms for treatment group, centre, patient age, baseline score, ED duration, baseline ED severity, and smoking status. All statistical tests were two sided and performed at the 5% significance level. A total of 217 men (mean age: 46 years; mean duration of ED: 5.7 years; mean duration of MS: 10.4 years) from 20 sites in the United States and Europe received treatment with sildenafil (n = 104) or placebo (n = 113) for 12 weeks.

The patients in the two treatment groups had similar demographic characteristics with respect to age, duration of ED, duration of MS, and EDSS score (table 1), but men in the placebo group reported more frequent use of antihypertensive agents and less use of corticosteroids compared with the treatment group.

At the end of the 12 week period, almost two thirds of men (64%) receiving sildenafil were taking the 100 mg dose, compared with 32% on the 50 mg dose, and 4% on the 25 mg dose.

In the placebo group, 96% of men were taking the 100 mg dose, and 4% were taking the 50 mg dose. Download figure Open in new tab Download powerpoint. Download figure Open in new tab

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Download figure Open in new tab Download powerpoint.

Quality of life variables that improved with sildenafil treatment (black bars) compared with placebo (white bars). Overall, 26/206 (13%) subjects discontinued the OLE phase (fig 1), and of these 11/106 (10%) were sildenafil naive during the DB phase.

Of the 26 subjects who discontinued, 17 (8%) did so for reasons not related to treatment (AEs, n = 3; laboratory abnormalities, n = 1; lost to follow up, withdrawal of consent, other, n = 14).

The most common AEs are shown in table 2, and were comparable in nature and rate of occurrence to AEs reported in the DB phase of the study. Overall, 12 patients (6%) reported treatment emergent serious AEs during the OLE phase, most of which (n = 9) were relapses of MS or aggravation of MS symptoms, requiring hospitalisation. Seven subjects experiencing these relapses had received sildenafil during the DB phase of the study and two patients had received placebo.

In all cases, the subject returned to the study and completed the viagra price in mercury drugstore OLE phase without further worsening of the MS symptoms. None of the serious AEs were attributed to the study medication. Sildenafil significantly improved erectile function and the ability to engage in satisfactory sexual activity in men with ED due to MS.

Treatment with sildenafil was well tolerated, with 98% of the patients completing the study. Furthermore, oral sildenafil treatment resulted in significant improvements in both general and disease specific QoL variables, and the treatment therefore represents an important advance in the management of ED in this group of patients. Although men participating in this study were ambulatory, indicative of their relatively mild spinal cord involvement (Kurtzke EDSS 13, 14 Although the pharmacological mechanism of sildenafil is not expected to affect desire and orgasmic function, both domains showed improvement in this current study. These improvements are thought to happen secondary to improvements in erectile function, with men feeling good about their ability to resume sexual activity and sildenafil enabling them to sustain an erection until orgasm is achieved.

During the DB phase, AEs associated with sildenafil use occurred more frequently than in the placebo group, raising an issue about patients being unblinded and introducing bias when answering subjective questionnaires. However, this is a potential issue in many clinical trials and the incidence of AEs related to sildenafil treatment in this study was comparable to that in other trials, for example, in patients with diabetes, 20 depression, 21 or SCI 22 (range, 31–40%). Efficacy of sildenafil is comparable in men with ED and concomitant MS (current study) or SCI. 13, 14 The ability to achieve an erection (IIEF Q3) was improved 1.6-fold in MS patients and 1.8-fold in SCI patients, whereas the ability to maintain an erection (IIEF Q4) improved 1.9-fold in MS patients and 2.1-fold in SCI patients.

From the GEQ, the percentage of MS patients reporting improved erections was 90% for sildenafil users compared with 24% for placebo users; the percentage of SCI patients reporting improved erections was 75% for sildenafil users compared with 7% of placebo users. These data demonstrate that patients with ED due to spinal disease respond well to treatment with sildenafil. The results are comparable to or better than a population of patients with ED of mixed etiology (72–79%) 23 and markedly higher than in patients with diabetes mellitus (48–72%), 24 whose poorly preserved vasculature might be the main reason for low efficacy.

Interestingly, there appears to be a greater efficacy of sildenafil in patients with MS than in patients with diabetes, since 64% of men with MS preferred the 100 mg dose, compared with 75% of men with diabetes choosing that dose. Moreover, greater efficacy in patients with MS may be due to the fact that sildenafil acts peripherally, and although pyschogenically driven erections are likely to have been impaired by spinal cord disease, reflexogenic responses, subserved by sacral segmental pathways, are still intact.

The average age of patients in this study is relatively young and with healthy peripheral neurovasculature a good erectile response is obtained by reflex mechanisms and what psychogenic responsiveness remains available.

Sildenafil was well tolerated in this study, as the majority of AEs reported during both phases were mild to moderate in severity and non-serious.

AEs were those known to be associated with the mechanism of action of sildenafil, such as headache, vasodilation, and dyspepsia. The following clinical investigators contributed to this study: Dr Hans Jacob Hansen, Arhus, Denmark; Dr Andreo Larsen, Helsinki, Finland; Dr Ragnar Stien, Moelv, Norway; Dr Morten Andersen, Moelv, Norway; Dr Sten Fredrikson, Huddunge,

Sweden

Warnings and Precautions, Effects on the Eye (5.3) 08/2017.

VIAGRA is a phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED) (1) DOSAGE AND ADMINISTRATION.

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 30 minutes to 4 hours before sexual activity (2.1) Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg (2.1) Maximum recommended dosing frequency is once per day (2.1) DOSAGE FORMS AND STRENGTHS. Tablets: 25 mg, 50 mg, 100 mg (3) CONTRAINDICATIONS.

Administration of VIAGRA to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form.

VIAGRA was shown to potentiate the hypotensive effect of nitrates (4.1, 7.1, 12.2) Known hypersensitivity to sildenafil or any component of tablet (4.2) Administration with guanylate cyclase (GC) stimulators, such as riociguat (4.3) WARNINGS AND PRECAUTIONS. Patients should not use VIAGRA if sexual activity is inadvisable due to cardiovascular status (5.1) Patients should seek emergency treatment if an erection lasts >4 hours.

Use VIAGRA with caution in patients predisposed to priapism (5.2) Patients should stop VIAGRA and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION). VIAGRA should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a "crowded" optic disc may also be at an increased risk of NAION. (5.3) Patients should stop VIAGRA and seek prompt medical attention in the event of sudden decrease or loss of hearing (5.4) Caution is advised when VIAGRA is co-administered with alpha-blockers or anti-hypertensives. Concomitant use may lead to hypotension (5.5) Decreased blood pressure, syncope, and prolonged erection may occur at higher sildenafil exposures. In patients taking strong CYP inhibitors, such as ritonavir, sildenafil exposure is increased. Decrease in VIAGRA dosage is recommended (2.4, 5.6) ADVERSE REACTIONS.

Most common adverse reactions (? 2%) include headache, flushing, dyspepsia,

abnormal

VIAGRA can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives (4.1, 5.5, 7.1, 7.2, 7.3, 12.2) With concomitant use of alpha blockers, initiate VIAGRA at 25 mg dose (2.3) CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase VIAGRA exposure (2.4, 7.4, 12.3) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period (2.4, 5.6) Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg (2.4, 7.4) USE IN SPECIFIC POPULATIONS.

Geriatric use: Consider a starting dose of 25 mg (2.5, 8.5) Severe renal impairment: Consider a starting dose of 25 mg (2.5, 8.6) Hepatic impairment: Consider a starting dose of 25 mg (2.5, 8.7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE.

4.3 Concomitant Guanylate Cyclase (GC) Stimulators.

5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives.

5.6 Adverse Reactions with the Concomitant Use of Ritonavir. 5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies. 5.9 Counseling Patients About Sexually Transmitted Diseases.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility.

VIAGRA is indicated for the treatment of erectile dysfunction. 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 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day.

Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. VIAGRA was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [ see Contraindications (4.1), Drug Interactions (7.1), and Clinical Pharmacology (12.2) ] . 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 25 mg [ see Warnings and Precautions (5.5), Drug Interactions (7.2), and Clinical Pharmacology (12.2) ]. The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [ see Warnings and Precautions (5.6), Drug Interactions (7.4), and Clinical Pharmacology (12.3) ]. Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold [ see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ].

Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance see Use in Specific Populations (8.5, 8.6, 8.7) and Clinical Pharmacology (12.3) ] .

VIAGRA is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to 25 mg, 50 mg, or 100 mg of sildenafil.

Tablets are debossed with PFIZER on one side and VGR25, VGR50 or VGR100 on the other to indicate the dosage strengths. Consistent with its known effects on the nitric oxide/cGMP pathway [ see Clinical Pharmacology (12.1, 12.2) ], VIAGRA was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated.

After patients have taken VIAGRA, it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Dosage and Administration (2.3), Drug Interactions (7.1), and Clinical Pharmacology (12.2) ].

VIAGRA is contraindicated in patients with a known hypersensitivity to sildenafil, as contained in VIAGRA and REVATIO, or any component of the tablet.

Hypersensitivity reactions have been reported, including rash and urticaria [ see Adverse Reactions (6.1) ] . 4.3 Concomitant Guanylate Cyclase (GC) Stimulators.

Do not use VIAGRA in patients who are using a GC stimulator, such as riociguat.

PDE5 inhibitors, including VIAGRA, may potentiate the hypotensive effects of GC stimulators.

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. The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment. 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 (12.2) ].

While viagra price in mercury drugstore 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.

Use with caution in patients with the following underlying conditions which 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 are 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 170/110 mmHg); Patients with cardiac failure or coronary artery disease causing unstable angina.

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. 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).

However, there are no controlled clinical data on the safety or efficacy of VIAGRA in patients with sickle cell or related anemias.

Physicians should advise patients to stop use of all phosphodiesterase type 5 (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 rare condition and 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. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ? 50. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20).

Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare post-marketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [ see Adverse Reactions (6.2) ].

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including VIAGRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks.

Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including VIAGRA, for this uncommon condition. There are no controlled clinical data on the safety or efficacy of VIAGRA in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution.

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 (6.1, 6.2) ].

5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives. Caution is advised when 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 occur.

In some patients, concomitant use of these two drug classes can lower blood pressure significantly [ see Drug Interactions (7.2) and Clinical Pharmacology (12.2) ] leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).

Consideration should be given to the following: Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.

In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [ see Dosage and Administration (2.3) ].