PATIENT SUMMARY OF INFORMATION ABOUT

This summary contains important information about VIAGRA®. 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.

 

• HOW SEX AFFECTS THE BODY

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.

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ADVERSE REACTIONS

CLINICAL TRIALS:

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:

Viagra

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 may reduce 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 Cmax 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).

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 Cmax 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 .

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Precautions

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).

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.

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Indication and Usage

INDICATION AND USAGE

VIAGRA is indicated for the treatment of erectile dysfunction.

 

CONTRAINDICATIONS

Consistent with its known effects on the nitric oxide/cGMP pathway, 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). 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.

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.

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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 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.

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-methyl-7-oxo-3-propyl-1Hpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula: