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VIAGRA (sildenafil citrate)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Oral

Tablets 25 mg, 50 mg and 100 mg

The tablets also contain the following non-medicinal ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake.

Indications And Clinical Use

VIAGRA* (sildenafil citrate) is indicated for:

  • the treatment of erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.

Contraindications

VIAGRA (sildenafil citrate) has been shown to potentiate the hypotensive effects of nitrates in healthy volunteers and in patients, and is therefore contraindicated in patients who are taking any type of nitrate drug therapy, or who utilize short-acting nitrate-containing medications, due to the risk of developing potentially life-threatening hypotension. The use of organic nitrates, either regularly and/or intermittently, in any form (e.g. oral, sublingual, transdermal, by inhalation) is absolutely contraindicated (see ACTION AND CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION).

After patients have taken VIAGRA, it is unknown when nitrates, if necessary, can be safely administered. Plasma levels of sildenafil at 24 hours post-dose are much lower (2 ng/mL) than at peak concentration (440 ng/mL). In the following patients: age >65, hepatic impairment (e.g. cirrhosis), severe renal impairment (e.g. CLcr <30 mL/min), and concomitant use of potent cytochrome P-450 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 (see DETAILED PHARMACOLOGY, Pharmacodynamic Studies).

Treatments for erectile dysfunction should not be generally used in men for whom sexual activity is inadvisable (see also WARNINGS AND PRECAUTIONS).

VIAGRA is contraindicated in patients with a known hypersensitivity to any component of the tablet (see PHARMACEUTICAL INFORMATION).

VIAGRA is contraindicated in patients with erectile dysfunction with previous episode of non-arteritic anterior ischaemic optic neuropathy (NAION) (see WARNINGS AND PRECAUTIONS).

The co-administration of PDE5 inhibitors, including VIAGRA*, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may lead to potentially life-threatening episodes of symptomatic hypotension or syncope.

Warnings And 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.

Cardiovascular

As with all treatments for erectile dysfunction, there is a potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease, including hypertension (BP>140/90). Therefore, treatments for erectile dysfunction, including VIAGRA (sildenafil citrate), should not be generally administered in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

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 <90/50 at rest) or hypertension (BP >170/110 at rest)
  • Patients with cardiac failure or coronary artery disease causing unstable angina

(see ACTION AND CLINICAL PHARMACOLOGY)

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the coadministration may lead to symptomatic hypotension in a few susceptible individuals (see DRUG INTERACTIONS). In order to minimize the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at lower doses should be considered. In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.

Hematologic

In clinical trials, sildenafil has been shown to have systemic vasodilatory properties that result in transient decreases in blood pressure (see DETAILED PHARMACOLOGY). This is of little or no consequence in most patients. However, prior to prescribing sildenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.

In humans, VIAGRA (sildenafil citrate) has no effect on bleeding time when taken alone or with acetylsalicylic acid. 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 (see ACTION AND CLINICAL PHARMACOLOGY).

There is no safety information on the administration of VIAGRA to patients with bleeding disorders or active peptic ulceration. Therefore, VIAGRA should be administered with caution to these patients.

Hepatic/Biliary/Pancreatic

In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.

A starting dose of 25 mg should be considered in patients with hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION).

Ophthalmologic

Patients should stop taking PDE5 inhibitors, including VIAGRA, and consult their physician immediately if they experience a decrease in, or sudden loss of, vision in one or both eyes. Postmarketing reports of sudden loss of vision have occurred rarely, in temporal association with the use of PDE5 inhibitors. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use.

Individuals who have already experienced NAION are at increased risk of NAION recurrence. PDE 5 inhibitors, including VIAGRA, are not recommended in patients with male erectile dysfunction with a previous episode of NAION (see CONTRAINDICATIONS). 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. (see ACTION AND CLINICAL PHARMACOLOGY).
A small percentage of patients experience visual effects (e.g. impairment of colour discrimination, increased perception to light, blurred vision, eye pain, ocular redness) after taking VIAGRA. If this happens, then the patient should not operate a motor vehicle or any heavy machinery until the adverse effects disappear (see ACTION AND CLINICAL PHARMACOLOGY).

Rare cases of central serous chorioretinopathy have been reported during the post-marketing period in temporal association with the use of sildenafil citrate. It is not known if medical and other facts were reported that may have also played a role in the development of the condition. It is not possible to determine whether the development of the condition was related directly to the use of sildenafil, to the patient’s possible underlying risk factors, a combination of these factors, or to other factors. These cases of central serous chorioretinopathy in patients receiving sildenafil did not provide evidence of serious or permanent alteration in visual function. (See POST-MARKET ADVERSE DRUG REACTIONS).

Otologic

Sudden decrease or loss of hearing has been reported in a few number of postmarketing and clinical trials cases with the use of PDE5 inhibitors, including VIAGRA. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS, POST-MARKET ADVERSE DRUG REACTIONS and PART III CONSUMER INFORMATION). Physicians should advise patients to stop taking VIAGRA and seek prompt medical attention in case of sudden decrease or loss of hearing.

Renal

In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) was not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment.

A starting dose of 25 mg should be considered in patients with severe renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION).

Sexual Function/Reproduction

Although priapism had not been reported during clinical trials, prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently during the post-marketing surveillance 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 (see ADVERSE REACTIONS).

Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma or leukemia).

The safety and efficacy of combinations of VIAGRA with other PDE5 inhibitors, or other pulmonary arterial hypertension (PAH) treatments containing sildenafil (REVATIO), or other agents for the treatment of erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Skin/Appendages

Rare cases of Stevens-Johnson’s Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported during the post-marketing period.

Special Populations

Women, Nursing Mothers, Pregnancy: VIAGRA is not indicated for use in women. There are no adequate and well-controlled studies in pregnant or lactating women.

Pediatrics: VIAGRA is not indicated for use in children.

Geriatrics (> 65 years of age): Healthy elderly volunteers had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in younger volunteers (18 to 45 years). Since higher plasma levels may increase both the pharmacological action and incidence of some adverse events, a starting dose of 25 mg should be considered (see ACTION AND CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION).

Adverse Reactions

Adverse Drug Reaction Overview

Pre-Marketing Experience:

VIAGRA (sildenafil citrate) was administered to over 3700 patients (aged 19-87 years) during 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.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
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:

Table 1. Adverse Events Reported by ≥2% of Patients Treated with VIAGRA or Placebo in PRN Flexible-Dose Phase II/III Studies
Adverse EventPercentage of Patients Reporting Event
VIAGRA (n=734)PLACEBO (n=725)
Headache15.8%3.9%
Flushing10.5%0.7%
Dyspepsia6.5%1.7%
Nasal Congestion4.2%1.5%
Respiratory Tract Infection4.2%5.4%
Flu Syndrome3.3%2.9%
Urinary Tract Infection3.1%1.5%
Abnormal Vision*2.7%0.4%
Diarrhea2.6%1.0%
Dizziness2.2%1.2%
Rash2.2%1.4%
Back Pain2.2%1.7%
Arthralgia2.0%1.5%

* Abnormal Vision: Mild and transient changes, predominantly impairment of colour discrimination (blue/green), but also increased perception to light or blurred vision.

At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently.

Less Common Clinical Trial Adverse Drug Reactions (<2%)

The following events occurred in <2% of patients in in phase II/III controlled clinical trials where a causal relationship is uncertain:

Autonomic:sweating, dry mouth;
Cardiovascular:abnormal electrocardiogram, angina pectoris, arrhythmia, AV block, cardiac arrest, cardiomyopathy, heart failure, hypertension, hypotension, palpitation, postural hypotension, myocardial ischemia, syncope, tachycardia, varicose vein, vascular anomaly;
Central & Peripheral
Nervous System:
tremor, abnormal dreams, anxiety, agitation, ataxia, depression, insomnia, nervousness, somnolence, paresthesia, vertigo, speech disorder, reflexes decreased, hyperesthesia, neuropathy, migraine, myasthenia, oculogyric crisis, neuralgia, hypertonia;
Gastrointestinal:vomiting, gastritis, gastrointestinal disorder, flatulence, increased appetite, gastroenteritis, stomatitis, eructation, dysphagia, colitis, glossitis, constipation, rectal hemorrhage, mouth ulceration, esophagitis, rectal disorder, gingivitis, tooth disorder;
Hematopoietic:anemia and leukopenia;
Liver/Biliary:liver function tests abnormal, ALT increased;
Metabolic/Nutritional:edema, thirst, gout, hyperuricemia, hypoglycemic reaction, unstable diabetes, hyperglycemia, hyperlipidemia, hypernatremia;
Musculoskeletal:myalgia, bone disorder, arthrosis, arthritis, tendon rupture, tenosynovitis, bone pain, joint disorder, synovitis;
Respiratory:asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, respiratory disorder, carcinoma of lung, sputum increased, cough increased;
Skin/Appendages:skin carcinoma, skin disorder, skin hypertrophy, skin ulcer, contact dermatitis, exfoliative dermatitis, pruritus, urticaria, photosensitivity reaction, nail disorder, acne, herpes simplex, furunculosis;
Special Senses:Sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, eye pain, tinnitus, ear pain, lacrimation disorder, eye disorder, eye hemorrhage, ear disorder, cataract, dry eyes;
Urogenital:penile erection, other sexual dysfunction, cystitis, nocturia, balanitis, urinary frequency, breast enlargement, prostatic disorder, testis disorder, urinary incontinence, urinary tract disorder, urine abnormality, abnormal ejaculation, genital edema and anorgasmia;
Vascular Disorders:cerebrovascular disorder, cerebral thrombosis;
General:face edema, peripheral edema, chills, allergic reaction, asthenia, pain, infection, shock, hernia, accidental fall, abdominal pain, chest pain, accidental injury, intentional overdose.

Myocardial Infarction and Cardiovascular Mortality

In an analysis of double blind placebo controlled clinical trials encompassing over 700 person-years of observation on placebo and over 1300 person-years on sildenafil, there were no differences in the incidence rate of myocardial infarction (MI) or in the rate of cardiovascular mortality for patients receiving sildenafil compared to those receiving placebo. The rates of MI were 1.1 per 100 person-years for men receiving sildenafil and for those receiving placebo. The rates of cardiovascular mortality were 0.3 per 100 person-years for men receiving sildenafil and those receiving placebo.

Clinical Trial Adverse Drug Reactions Reported in 74 Double-Blind Placebo-Controlled Phase II/III/IV Studies

When VIAGRA was taken as recommended in 74 randomized double-blind, placebo-controlled (DBPC) Phase II/III/IV studies, adverse reactions reported by ≥2% of patients treated with VIAGRA (n=9,570) and more frequently than placebo (n=7,237) were headache, flushing, dyspepsia, nasal congestion and dizziness. The nature and frequency of adverse reactions reported by ≥2% of patients in this pooled dataset of 74 DBPC studies was consistent with the adverse reactions reported in the 6 flexible-dose studies detailed above in Table 1.

The following adverse reactions occurred in <2% of patients in the 74 DBPC clinical trials.

Cardiac disorders:

palpitations, tachycardia;

Eye disorders:

vision blurred, chromatopsia, cyanopsia, photophobia, visual disturbance, photopsia, ocular hyperaemia, eye pain, visual brightness, abnormal sensation in eye, asthenopia, conjunctival hyperaemia, dry eye, erythropsia, eye disorder, eye irritation, eye edema, eyelid edema, eye swelling, halo vision, xanthopsia;

Gastrointestinal disorders:

nausea, dry mouth, abdominal pain upper, vomiting, gastroesophageal reflux disease, oral hypoaesthesia;

General conditions and administration site conditions:

feeling hot, irritability;

Immune system disorders:

hypersensitivity;

Infections and infestations:

rhinitis;

Investigations:

heart rate increased;

Musculoskeletal and connective tissue disorders:

pain in extremity, myalgia;

Nervous system disorders:

syncope, somnolence;

Reproductive system and breast disorders:

erection increased;

Respiratory, thoracic and mediastinal disorders:

epistaxis, sinus congestion, nasal oedema, nasal dryness, throat tightness;

Skin and subcutaneous tissue disorders:

rash;

Vascular disorders:

hot flush, hypotension.

Post-Market Adverse Drug Reactions

Reports of adverse events temporally associated with VIAGRA during post-marketing surveillance that are not listed above and for which the causal relationship is unknown, include the following:

Cardiovascular:
Epistaxis; serious cardiovascular events - including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, and transient ischemic attack - have been reported. Most of these patients had pre-existing cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of VIAGRA without sexual activity. Others were reported to have occurred hours to days after the use of VIAGRA with sexual activity. It is not possible to determine whether these events are related directly to VIAGRA, to sexual activity, to the patient's underlying cardiovascular disease, to combination of these factors, or to other factors (see WARNINGS AND PRECAUTIONS).

Central & Peripheral
Nervous System:
seizure, seizure recurrence, transient global amnesia;
Gastrointestinal:vomiting;
Urogenital:prolonged erection, priapism (see WARNINGS AND PRECAUTIONS) and hematuria;
Skin / Appendages:Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
Special Senses:diplopia, temporary vision loss/decreased vision, blurred vision, Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION) , retinal vein occlusion, visual field defect, eye pain, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease of bleeding, vitreous detachment/traction and paramacular edema.

Cases of sudden decrease or loss of hearing have been reported post-marketing in temporal association with the use of PDE5 inhibitors, including VIAGRA. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these events are related directly to the use of VIAGRA, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors (see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and PART III CONSUMER INFORMATION).

Rare cases of central serous chorioretinopathy have been reported during the post-marketing period in temporal association with the use of sildenafil citrate. It is not known if medical and other facts were reported that may have also played a role in the development of the condition. It is not possible to determine whether the development of the condition was related directly to the use of sildenafil, to the patient’s possible underlying risk factors, a combination of these factors, or to other factors. These cases of central serous chorioretinopathy in patients receiving sildenafil did not provide evidence of serious or permanent alteration in visual function. (SEE WARNINGS AND PRECAUTIONS).

Drug Interactions

Serious Drug Interactions
 

  • Use of organic nitrates in any form is absolutely contraindicated (see Contraindications section)

Overview

In vitro studies:
Sildenafil metabolism is principally mediated by the cytochrome P-450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route) (see ACTION AND CLINICAL PHARMACOLOGY). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.

Sildenafil is a weak inhibitor of the cytochrome P-450 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 the substrates of these isoenzymes.

In vivo studies:
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

Drug-Drug Interactions

Effects of Other Drugs on 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, angiotensin converting enzyme (ACE) inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

In healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principle circulating metabolite.

CYP3A4 Inhibitors
The concomitant use of potent cytochrome P-450 3A4 inhibitors (e.g. erythromycin, saquinavir, ritonavir, ketoconazole, itraconazole) as well as the non-specific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil (see DOSAGE AND ADMINISTRATION, DETAILED PHARMACOLOGY).

When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg b.i.d. for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC).

When the dose of sildenafil for subjects receiving potent CYP3A4 inhibitors was administered as recommended, the maximum free plasma sildenafil concentration did not exceed 200 nM for any individual and was consistently well tolerated.

In a study of healthy male volunteers, co-administration of the endothelin antagonist bosentan, (an inducer of CYP3A4 [moderate], CYP2C9 and possibly of CYP2C19) at steady state (125 mg twice a day) with sildenafil at steady state (80 mg three times a day) resulted in 62.6% and 55.4% decrease in sildenafil AUC and Cmax, respectively. Sildenafil increased bosentan AUC and Cmax by 49.8% and 42%, respectively. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma concentrations of sildenafil.

Cimetidine (800 mg), a cytochrome P450 inhibitor and a non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers.

Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). However, there was no increased incidence of adverse events in these patients.

HIV Protease Inhibitor
In addition, coadministration of the HIV protease inhibitor saquinavir, also CYP3A4 inhibitor, at steady state (1200 mg t.i.d) with sildenafil (100 mg single dose) resulted in a 140 % increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole, itraconazole would be expected to have still greater effects (see DOSAGE AND ADMINISTRATION).

Coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P-450 inhibitor, at steady state (500 mg b.i.d) with sildenafil (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 the marked effects of ritonavir on a broad range of P-450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics (see DOSAGE AND ADMINISTRATION).

CYP3A4 Inducers
It can be expected that concomitant administration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of sildenafil.

CYP2C9 Substrate
No significant interactions were shown with tolbutamide (single 250 mg dose) or warfarin (single 40 mg dose), both of which are metabolized by CYP2C9, when co-administered with 50 mg sildenafil.

Antacids
In normal healthy male volunteers, co-administration of single doses of antacid (magnesium hydroxide/aluminium hydroxide) with sildenafil did not affect the AUC, Cmax, elimination rate constant, or subsequent half-life of sildenafil. The Tmax was reduced by 0.42 hours.

Effect of VIAGRA on Other Drugs

Alpha-blockers
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, for 25 mg, 50 mg, or 100 mg respectively, were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals (see WARNINGS AND PRECAUTIONS).

Some alpha-blockers and antidepressants have reported priapism or prolonged/painful erections in their labels.

Bleeding Time
VIAGRA (50 mg) did not potentiate the increase in bleeding time, measured using a standard simplate method, caused by acetylsalicylic acid (150 mg).

Use with Other Concomitant Therapies:

Antihypertensives
When VIAGRA (100 mg) was co-administered with amlodipine, 5 mg or 10 mg, in hypertensive patients, the mean additional reduction of supine blood pressure was 8 mm Hg systolic and 7 mm Hg diastolic (see ACTION AND CLINICAL PHARMACOLOGY).

Patients on multiple antihypertensive medications were included in the pivotal clinical trials for VIAGRA (sildenafil citrate). Analysis of the safety database was carried out after pooling of the following classes of antihypertensive medication: diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive medicinal products (vasodilator and centrally-acting), adrenergic neurone blockers, calcium channel blockers and alpha-adrenoceptor blockers. The analysis showed no differences in the adverse effect profile of patients taking VIAGRA with and without antihypertensive medication.

A large controlled study was performed in men with erectile dysfunction and arterial hypertension who were taking combinations of diuretics, beta blockers, ACE inhibitors and calcium channel blockers. The incidence rate of all adverse events, including those possibly related to hypotensive episodes, was consistent with observations in other patient populations. Also, there was no evidence of an increased incidence rate of any adverse event in the subgroups taking 2 antihypertensive agents and 3 or more antihypertensive agents. There was no indication of additional safety risk of sildenafil use in this subject population (see DETAILED PHARMACOLOGY).

Bosentan
Sildenafil at steady state (80 mg three times a day) resulted in a 49.8% increase in bosentan AUC and a 42% increase in bosentan Cmax (125 mg twice a day) (see DRUGS INTERACTIONS).

Drug-Food Interactions

Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism may give rise to modest increases in plasma levels of sildenafil.

VIAGRA (sildenafil citrate) can be taken with or without food. However, when VIAGRA is taken with a high-fat meal, the rate of absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. AUC is decreased by 11%. The patient may find that it takes longer to work if taken with a high-fat meal (see ACTION AND CLINICAL PHARMACOLOGY).

Dosage And Administration

Dosing Considerations

The following factors are associated with increased plasma levels (AUC) of sildenafil:

  • age 65 years or over (40%)
  • hepatic impairment (e.g. cirrhosis: 84%)
  • severe renal impairment (e.g. creatinine clearance <30 mL/min: 100%) concomitant use of potent cytochrome P-450 3A4 inhibitors (e.g. erythromycin: 182%; saquinavir: 210%; ritonavir: 1000%). It can also be expected that more potent cytochrome P-450 3A4 inhibitors such as ketoconazole and itraconazole would result in increased levels of sildenafil.

(see Recommended Dose and Dose Adjustment, ACTION AND CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS).

VIAGRA (sildenafil citrate) has been shown to potentiate the hypotensive effects of nitrates in healthy volunteers and in patients, and is therefore contraindicated in patients who are taking any type of nitrate drug therapy, or who utilize short-acting nitrate-containing medications, due to the risk of developing potentially life-threatening hypotension. The use of organic nitrates, either regularly and/or intermittently, in any form (e.g. oral, sublingual, transdermal, by inhalation) is absolutely contraindicated (see ACTION AND CLINICAL PHARMACOLOGY, CONTRAINDICATIONS).

Recommended Dose and Dosage Adjustment

For most patients, the recommended dose of VIAGRA is 50 mg taken as needed. The maximum recommended dose is 100 mg. Dosage may be decreased to 25 mg if necessary.

Since higher plasma levels may increase both efficacy and the incidence of adverse events, a starting dose of 25 mg should be considered in patients, age 65 years or over, on concomitant CYPA4 inhibitors, with severe renal impairment, with hepatic impairment and on ritonavir (see Dosing Considerations above, ACTION AND CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS).

The concomitant use of the potent cytochrome P-450 3A4 inhibitor, ritonavir is associated with a 1000% (11-fold) increase in plasma levels (AUC) of sildenafil. Given the extent of the interaction with patients receiving concomitant therapy with ritonavir, it is recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48-hour period (see WARNINGS AND PRECAUTIONS).

Administration

To be taken as needed approximately 30 – 60 minutes before sexual activity. However, VIAGRA may be taken anywhere from 0.5 hour to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

In studies with healthy volunteers of single doses of up to 800 mg, adverse events 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 not eliminated in the urine.

Treatment of Priapism
Patients should be instructed to report any erections persisting for more than 4 hours to a physician. The treatment of priapism/prolonged erection should be according to established medical practice. Physicians may refer to two suggested protocols for detumescence presented below.

Detumescence Protocols

  1. Aspirate 40 to 60 mL blood from either left or right corpora using vacutainer and holder for drawing blood. Patient will often detumesce while aspirating. Apply ice for 20 minutes post aspiration if erection remains.

If procedure 1) is unsuccessful, then try procedure 2).
 

  1. Put patient in supine position. Dilute 10 mg phenylephrine into 20 mL distilled water for injection (0.05%). With an insulin syringe, inject 0.1 to 0.2 mL (50-100 µg) into the corpora every 2 to 5 minutes, until the detumescence occurs. The occasional patient may experience transient bradycardia and hypertension when given phenylephrine injections, therefore monitor patient’s blood pressure and pulse every 10 minutes. Patients at risk include those with cardiac arrhythmias and diabetes. Refer to the prescribing information for phenylephrine before use. Do not give phenylephrine to patients on MAO inhibitors. When phenylephrine is used within the first 12 hours of erection, the majority of patients will respond.

If procedure 2) is unsuccessful, then try procedure 3).
 

  1. If the above measures fail to detumesce the patient, a urologist should be consulted as soon as possible, especially if the erection has been present for many hours. If priapism is not treated immediateIy, penile tissue damage and/or permanent loss of potency may result.

Action And Clinical Pharmacology

Mechanism of Action

VIAGRA (sildenafil citrate) is a cGMP-specific phosphodiesterase type 5 (PDE5) inhibitor, used for the treatment of male erectile dysfunction.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum in response to sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.

Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for the biodegradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil produces increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and increased inflow of blood to the corpus cavernosum. Sildenafil, at recommended doses, has no effect in the absence of sexual stimulation.

Studies in vitro have shown that sildenafil has between 10 and 10,000-fold greater selectivity for PDE5 than for other phosphodiesterase isoforms namely PDEs 1, 2, 3, 4, and 6 and greater than 700-fold effect on PDE7-PDE11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. Sildenafil is about 10-fold as potent for PDE5 compared to PDE6, an isoenzyme found in the retina; this lower selectivity is thought to be the basis for colour vision abnormalities observed with higher doses or plasma levels of sildenafil (see WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

PDE5 is also found in lower concentrations in platelets, vascular and visceral smooth muscles, and skeletal muscle. The sildenafil-induced inhibition of PDE5 in these tissues appears to be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, and inhibition of platelet thrombus formation in vivo, and peripheral arterial-venous dilation in vivo (see WARNINGS AND PRECAUTIONS).

Pharmacodynamics

Effects of VIAGRA on Blood Pressure (BP):

Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease of 8.3/5.3 mm Hg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing. The effects are not related to dose or plasma levels. Larger effects were recorded among patients receiving concomitant nitrates (see CONTRAINDICATIONS).

Effects of VIAGRA on Cardiac Parameters:

Single oral doses of VIAGRA up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

Effects of VIAGRA on Erectile Response:

VIAGRA was studied in clinical trials of various designs. In fixed-dose clinical trials, 62%, 74%, and 82% of patients on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 25% on placebo (p <0.0001, see CLINICAL TRIALS).

In eight double-blind, placebo-controlled, cross-over studies using RigiScan® (a device used to objectively measure penile rigidity and duration of erections), erections during sexual stimulation improved significantly on VIAGRA compared to placebo. These studies included patients with organic etiologies (such as spinal cord injury and diabetes mellitus), and patients without an established organic cause. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post-dose.

All eight studies investigating the effects of sildenafil on penile plethysmography (RigiScan®) after visual sexual stimulation (VSS) under laboratory conditions, consistently showed that doses of up to 100 mg resulted in statistically significant improvements in duration of erections of 60% rigidity (considered hard enough for penetrative sexual intercourse), compared with placebo. In patients who respond, the median time to onset of erections (60% rigidity) in response to VSS, was 25 minutes after an oral dose of 50 mg sildenafil. The mean total duration of erections 60% rigidity at the base of the penis was 3, 24 and 32 minutes for subjects receiving placebo, 25 mg and 50 mg doses, respectively, when exposed to VSS for 2 hours.

VIAGRA increases couples’ ability to have sexual intercourse (see CLINICAL TRIALS).

Pharmacokinetics

Absorption: Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute bioavailability is 41% (range 25%-63%). The oral pharmacokinetics of VIAGRA is proportional over the recommended dose range studied (25 mg to 100 mg).

Sildenafil inhibits the human PDE5 enzyme in vitro by 50% at a concentration of 3.5 nM. In man, the mean maximum free plasma concentration of sildenafil following a single oral dose of 100 mg is approximately 18 ng/mL, or 38 nM.

When VIAGRA was administered with a high-fat meal, the rate of absorption was significantly decreased, with a 29% reduction in Cmax and a 60-minute delay in Tmax. The patient may find that it takes longer to work if taken with a high-fat meal. However, although it was statistically significant (AUC decreased by 11%), the decrease in the extent of absorption was not clinically relevant. The relative bioavailability fed/fasted was 89% (90% CI; 84-94%) (see DRUG INTERACTIONS).

Distribution: The mean steady state volume of distribution (Vss) for sildenafil is 105 litres, 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 the semen of healthy volunteers, less than 0.001% of the ingested dose may appear in the semen of patients 90 minutes after drug intake.

Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil at the N-methyl piperazine moiety. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency against PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 hours.

Excretion: The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered dose) and to a lesser extent in the urine (approximately 13% of the administered dose).

Special Populations and Conditions

Geriatrics: Healthy elderly subjects (65 years or older) had a reduced clearance of sildenafil, resulting in approximately 90 % higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40 %.

Hepatic Insufficiency: In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Since sildenafil clearance is reduced in geriatric patients (65 years or older), patients with renal impairment or patients with hepatic impairment, a starting dose of 25 mg should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg or 100 mg (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).

Renal Insufficiency: In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment.

In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 200 % and 79 % respectively in subjects with severe renal impairment compared to subjects with normal renal function.

Storage And Stability

Store at controlled room temperature between 15 and 30°C.

Special Handling Instructions

Not Applicable.

Dosage Forms, Composition And Packaging

VIAGRA (sildenafil citrate) - 25 mg Tablets (sildenafil citrate equivalent to 25 mg of sildenafil per tablet) are supplied as blue, rounded, diamond-shaped tablets marked 'PFIZER’ on one side and ‘VGR 25' on the other side and supplied as follows:

- Blister pack 4 tablets

VIAGRA - 50 mg Tablets (sildenafil citrate equivalent to 50 mg of sildenafil per tablet) are supplied as blue, rounded, diamond-shaped tablets marked ‘PFIZER’ on one side and 'VGR 50' on the other side, and supplied as follows:

- Blister pack 4 and 8 tablets

VIAGRA - 100 mg Tablets (sildenafil citrate equivalent to 100 mg of sildenafil per tablet) are supplied as blue, rounded, diamond-shaped tablets marked ‘PFIZER’ on one side and 'VGR 100' on the other side, and supplied as follows:

- Blister pack 4 and 8 tablets

 

Control #: 180624
26 May 2015

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