Viagra 25 MG (as sildenafil citrate) Oral Tablet
Generic Name: SILDENAFIL CITRATE
Brand Name: Viagra
- Substance Name(s):
- SILDENAFIL CITRATE
DRUG INTERACTIONS
7 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) 7.1 Nitrates Administration of VIAGRA with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated.
Consistent with its known effects on the nitric oxide/cGMP pathway, VIAGRA was shown to potentiate the hypotensive effects of nitrates [see Dosage and Administration (2.3), Contraindications (4.1), Clinical Pharmacology (12.2) ].
7.2 Alpha-blockers Use caution when co-administering alpha-blockers with VIAGRA because of potential additive blood pressure-lowering effects.
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 Dosage and Administration (2.3),Warnings and Precautions (5.5), Clinical Pharmacology (12.2) ].
7.3 Amlodipine When VIAGRA 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [see Warnings and Precautions (5.5), Clinical Pharmacology (12.2) ].
7.4 Ritonavir and other CYP3A4 inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC).
It is therefore recommended not to exceed a maximum single dose of 25 mg of VIAGRA in a 48 hour period [see Dosage and Administration (2.4), Warnings and Precautions (5.6), Clinical Pharmacology (12.3) ].
Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil Cmax and AUC, respectively.
Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively.
Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir.
A starting dose of 25 mg of VIAGRA should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3) ].
7.5 Alcohol In a drug-drug interaction study sildenafil 50 mg given with alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [see Clinical Pharmacology (12.2) ].
OVERDOSAGE
10 In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities 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.
DESCRIPTION
11 VIAGRA (sildenafil citrate), 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 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.
Chemical Structure
CLINICAL STUDIES
14 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.
Efficacy Endpoints in Controlled Clinical Studies 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.
Efficacy Results from Controlled Clinical Studies The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, 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 6 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 6.
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 7.
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.
Overall treatment p<0.0001 Figure 7.
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.
Figure 6 Figure 6 Figure 7 Efficacy Results in Subpopulations in Controlled Clinical Studies 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 anti-hypertensives/diuretics.
HOW SUPPLIED
16 /STORAGE AND HANDLING VIAGRA (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil and debossed on the obverse and reverse sides as follows: 25 mg 50 mg 100 mg Obverse VGR25 VGR50 VGR100 Reverse PFIZER PFIZER PFIZER Bottle of 30 NDC-0069-4200-30 NDC-0069-4210-30 NDC-0069-4220-30 Bottle of 100 N/A NDC-0069-4210-66 NDC-0069-4220-66 Carton of 30 (1 tablet per Single Pack ) N/A NDC 0069-4210-33 NDC 0069-4220-33 Recommended Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Warnings and Precautions, Effects on the Eye (5.3) 08/2017
GERIATRIC USE
8.5 Geriatric Use 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 young volunteers (18–45 years) [see Clinical Pharmacology (12.3) ].
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 [see Clinical Pharmacology (12.3) ].
Of the total number of subjects in clinical studies of Viagra, 18% were 65 years and older, while 2% were 75 years and older.
No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects.
However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [see Dosage and Administration (2.5) ].
DOSAGE FORMS AND STRENGTHS
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.
Tablets: 25 mg, 50 mg, 100 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action 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 enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.
Sildenafil has no direct relaxant effect on isolated human 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.
Binding Characteristics 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).
Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3.
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 [see Clinical Pharmacology (12.2) ].
In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle.
The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.
INDICATIONS AND USAGE
1 VIAGRA is indicated for the treatment of erectile dysfunction.
VIAGRA is a phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED) (1)
PEDIATRIC USE
8.4 Pediatric Use VIAGRA is not indicated for use in pediatric patients.
Safety and effectiveness have not been established in pediatric patients.
PREGNANCY
8.1 Pregnancy Pregnancy Category B.
VIAGRA is not indicated for use in women.
There are no adequate and well-controlled studies of sildenafil in pregnant women.
Risk Summary Based on animal data, VIAGRA is not predicted to increase the risk of adverse developmental outcomes in humans.
Animal Data 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 Maximum Recommended Human Dose (MRHD) on a mg/m2 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.
WARNING AND CAUTIONS
5 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) 5.1 Cardiovascular 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 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.
5.2 Prolonged Erection and Priapism 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.
5.3 Effects on the Eye 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.
5.4 Hearing Loss 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 Alpha-blockers 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) ].
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.
Anti-hypertensives VIAGRA has systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications.
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 (7.3) and Clinical Pharmacology (12.2) ].
5.6 Adverse Reactions with the Concomitant Use of Ritonavir 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.
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 reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [see Dosage and Administration (2.4), Drug Interactions (7.4), and Clinical Pharmacology (12.3) ].
5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies The safety and efficacy of combinations of VIAGRA with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied.
Such combinations may further lower blood pressure.
Therefore, the use of such combinations is not recommended.
5.8 Effects on Bleeding There have been postmarketing reports of bleeding events in patients who have taken VIAGRA.
A causal relationship between VIAGRA and these events has not been established.
In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin.
However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor).
In addition, 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.
The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration.
5.9 Counseling Patients About Sexually Transmitted Diseases 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Nitrates Physicians should discuss with patients the contraindication of VIAGRA with regular and/or intermittent use of nitric oxide donors, such as organic nitrates or organic nitrites in any form [see Contraindications (4.1) ].
Guanylate Cyclase (GC) Stimulators Physicians should discuss with patients the contraindication of VIAGRA with use of guanylate cyclase stimulators such as riociguat [see Contraindications (4.3) ].
Concomitant Use with Drugs Which Lower Blood Pressure 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 [see Warnings and Precautions (5.5) ].
Cardiovascular Considerations 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 [see Warnings and Precautions (5.1) ].
Sudden Loss of Vision 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 possible permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors.
Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye.
Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including VIAGRA, for this uncommon condition [see Warnings and Precautions (5.3) and Adverse Reactions (6.2) ].
Sudden Hearing Loss 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 Warnings and Precautions (5.4) and Adverse Reactions (6.2) ].
Priapism 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 [see Warnings and Precautions (5.2) ].
Avoid Use with other PDE5 Inhibitors Physicians should inform patients not to take VIAGRA with other PDE5 inhibitors including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil.
Sildenafil is also marketed as REVATIO for the treatment of PAH.
The safety and efficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not been studied [see Warnings and Precautions (5.7) ].
Sexually Transmitted Disease 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 [see Warnings and Precautions (5.9) ].
DOSAGE AND ADMINISTRATION
2 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) 2.1 Dosage Information 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.
2.2 Use with Food VIAGRA may be taken with or without food.
2.3 Dosage Adjustments in Specific Situations 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) ].
2.4 Dosage Adjustments Due to Drug Interactions Ritonavir 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) ].
CYP3A4 Inhibitors 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) ].
2.5 Dosage Adjustments in Special Populations 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 <30 mL/minute) because administration of VIAGRA in these patients resulted in higher plasma levels of sildenafil [see Use in Specific Populations (8.5, 8.6, 8.7) and Clinical Pharmacology (12.3) ].