With VIAGRA^®, significantly higher percentages of men with ED reported improved erections versus placebo¹

Doses of VIAGRA^® (25 mg, 50 mg and 100 mg) significantly improved the erections of men with ED versus placebo.¹

Percentage (%) of patients reporting improvement of erections compared to placebo¹

Adapted from Montorsi F, et al. 1999.

End-of-treatment responses to the global efficacy question: ‘Did the treatment you received during the last 4 weeks improve your erections?’

In a 12-week, double-blind, randomised, placebo-controlled, fixed-dose study, 514 men (mean age 56 years) with ED were randomised to receive 50 mg or 100 mg of sildenafil or placebo. The primary aetiology of ED was determined to be organic in 32% of men, psychogenic in 25% or mixed in 43%. Sildenafil or placebo was taken in the home setting approximately 1 hour before sexual activity, not more than once daily. Efficacy was determined by responses to Question 3 (ability to achieve an erection) and Question 4 (ability to maintain an erection) of the 15-item IIEF.¹

IIEF Question 3 (Q3): Over the past 4 weeks (of your first visit) or since your last office visit when you attempted sexual intercourse, how often were you able to penetrate your partner?
ED: erectile dysfunction; IIEF: International Index of Erectile Function; NCD: non-communicable disease.

Improvement in erection hardness is correlated with better outcomes of overall satisfaction with VIAGRA^®2

• Sexual satisfaction reported by patients with ED treated with VIAGRA^® ranged from 85% to 89% at Grade 3 and Grade 4 erection hardness³
• Shift from Grade 3 to Grade 4 with VIAGRA^® is associated with overall satisfaction^2,3

Adapted from Mulhall J, et al, J Sex Med. 2007.

Improvement in sexual relationship and self-esteem with VIAGRA^®2

93% of men achieved SSI at Grade 4 erection hardness, which improved their sexual relationships.⁴

Adapted from Mulhall J, et al, J Sex Med. 2007.

Patients taking VIAGRA^® are more likely to refill their prescription⁶

A higher percentage of patients receiving VIAGRA^® refilled their ED medication during the study period than patients receiving vardenafil or tadalafil (P<0.001).⁵

      Adapted from Mulhall J, et al. J Sex Med. 2005.

Patients with an initial prescription claim for sildenafil, vardenafil, or tadalafil were identified in NDC Health’s Intelligent Health Repository. Medication refills, medication switching, and dose titration were analyzed. Logistic regression on the odds of refilling initial PDE5 medications was conducted controlling for patient age, presence of common comorbidities, initial number of tablets, and copay.⁵

ED: erectile dysfunction; EHS: Erection Hardness Score; IIEF: International Index of Erectile Function; LOCF: last observation carried forward; NCD: non-communicable disease; PDE-5: phosphodiesterase-5; SEAR: Self-Esteem and Relationship questionnaire; SSI: successful sexual intercourse.

Quick onset of action with VIAGRA^® film-coated tablets²

VIAGRA^®: Most men with ED achieved an erection in 30 minutes, some men did in 14 minutes and median of successful erection is 36 minutes.²

With VIAGRA^® 100 mg, 34.8% of men with ED achieved an erection that led to successful intercourse in 14 minutes (P=0.0343), and 67.8% of men with ED achieved an erection that led to successful intercourse in 30 minutes (P=0.0001).²

Male patients with ED (mean age: 60 years; mean ED duration: 7 years) who were successfully treated with VIAGRA^® 100 mg for 2 months or longer were randomised to VIAGRA^® (n=115) or placebo (n=113) for 4 weeks of double-blind treatment. Using a stopwatch, patients recorded the time needed to obtain an erection hard enough to attempt sexual intercourse (primary endpoint) after taking the study drug at least 2 hours after eating. The endpoint was the time to onset of an erection that led to successful intercourse. In this study, slightly more than one-half of a population of prior sildenafil responders achieved an erection that led to SSI within 20 minutes of sildenafil administration, suggesting that the onset of action of sildenafil can be less than 30 minutes in men with ED.²

ED: erectile dysfunction; NCD: non-communicable disease; SSI: successful sexual intercourse.

INDICATIONS AND DOSAGE¹

VIAGRA^® is indicated in adult men with ED.¹

VIAGRA^® tablets are available in 2 dosage strengths¹:

*Not the original size of the VIAGRA^® tablet.

For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity.¹

• VIAGRA^® may be taken 1hour before sexual activity¹
• Maximum recommended dosing frequency is once per day¹
• Based on effectiveness and tolerability, dosage may be increased to a maximum of 100 mg¹
• VIAGRA^® may be taken with or without food. If taken with food, the onset of activity may be delayed compared to the fasted state.¹

ED: erectile dysfunction; NCD: non-communicable disease.

Features of an ideal drug³

• Ease of administration
• Efficacy
• Good safety and tolerability across therapeutic range
• High selectivity for the site of action
• Rapid absorption and quick onset of action
• Short plasma t_1/2 period, which avoids accumulation on repeated doses

VIAGRA^® (Sildenafil citrate) was the first oral drug to possess the characteristics of an ideal oral drug.³

Patient’s requirements of an oral drug

Men with ED and their partners prefer an oral therapy that lasts long enough for successful intercourse to occur, works reliably every time when used and improves erection quality.⁴

Ranking of most important characteristic of ED treatment

Physician’s requirements of an oral drug

Physicians ranked effectiveness of a drug in difficult-to-treat populations as an important characteristic of ED therapy.⁴

Physician ranking of most important characteristics

Advantages of ODT

Be ready with VIAGRA^® ODT formulation for ED treatment³

• Increased convenience with easy uptake without water and rapidly disintegrating drug¹

Convenience of ED patients can be maintained by VIAGRA^® ODT formulation:⁵

• Ease of administration without water⁵
• Rapidly disintegrates within seconds⁵
• Increased treatment adherence to enhance treatment reliability⁵
• Lasts long enough (4 hours) for a successful sexual intercourse with quick onset of action¹
• Improves quality of life of ED patients and their partners by enhancing the sense of psychological well-being and sexual health⁵
• Median time to onset of action with VIAGRA^® is 25 min (range 12-37 min)¹

VIAGRA^® ODT formulation: An innovative way to treat ED³

The latest enhancement to an already well-known platform.⁵

Advantages of VIAGRA^® ODT formulation³:

• Disintegrates within seconds
• Provides an equivalent systemic exposure, similar to solid film-coated tablets
• Provides a convenient method of drug administration for patients who have daily fluid intake restrictions*

*In patients who have restrictions on daily fluid intake, such as those with reduced kidney function, congestive heart failure, endocrine system and adrenal gland disorders.³

Pharmacokinetics of a novel ODT formulation of VIAGRA® (Sildenafil citrate) ⁶

With VIAGRA^®, the median time to onset for those who obtained erections of 60% rigidity was 25 minutes¹

VIAGRA^® ODT when taken without water is considered bioequivalent to VIAGRA^® (Sildenafil citrate) film-coated tablets⁶

Thirty-six healthy male subjects 45 years of age or older were enrolled in this single-dose study.⁵ Three treatments were evaluated: VIAGRA^® 50 mg film-coated tablet with water, VIAGRA^® ODT 50 mg without water, and VIAGRA^® ODT 50 mg with water.¹

Onset of action and bioequivalence for VIAGRA^®(Sildenafil citrate) and vardenafil FCT with their respective ODT formulation^1,3,6

• The metabolite ratio remains the same with the film-coated tablet and ODT formulations, and the latter formulation provides an equivalent systemic exposure and represents a viable alternative to the conventional oral tablet formulation³
• When a quick onset of action is desired with vardenafil ODT, it should be taken with water, thus negating the benefits of the ODT formulation³
• Vardenafil ODT is not bioequivalent to the vardenafil film-coated tablet formulation, and thus should not be used as an equivalent³

In a Rigiscan study, the median time to onset for those who obtained erections of 60% rigidity was 25 minutes (range 12-37 minutes) on VIAGRA^® (Sildenafil citrate) film-coated tablets¹

Fast-disintegrating technology⁷

• Fast-disintegrating technology maximizes the porous structure of the tablet and incorporates disintegrating agents to assure that the tablet rapidly disintegrates in the mouth⁷

 ED: erectile dysfunction; ODT: orodispersible tablets.

Efficacy

At the end of the study, 44% of patients treated with VIAGRA^® ODT had no ED.⁴

With VIAGRA^® ODT significant improvement in erectile function in men with ED compared to placebo¹

60% of patients treated with VIAGRA^® ODT had statistically significant improvement in the IIEF-5 score compared to placebo (P<0.001).¹

Significant improvement in IIEF-5 scores from baseline with VIAGRA^® ODT compared to placebo¹

Annunziato MA, et al.: A blind, comparative, placebo-controlled, randomized study was developed in 106 patients with ED. They randomly received sildenafil orodispersible 50 mg (Group I) or placebo (Group II) 3 times per week, 1 hour before sexual activity, during 4 weeks. The efficacy was evaluated by IIEF-5 and the AE by poll. Sildenafil was superior to placebo, substantially improved the IIEF-5 scores, showing a statistically significant therapeutic response in the ED treatment and it was safe and well tolerated.¹

AE: adverse events; ED: erectile dysfunction; ODT: orodispersible tablet.

Dosing and Administration

VIAGRA^® ODT with added convenience³

The recommended dose of VIAGRA^® ODT is 50 mg which should be taken without water¹:

• Maximum recommended dosing frequency is once per day¹
• Should be taken 1 hour before sexual activity¹

VIAGRA^® ODT provides the same efficacy as VIAGRA^® film-coated tablets with ease of administration.¹

ODT: orodispersible tablet.

Viagra^® formulation

Viagra Film Coated Tablet and ODT Formulations

Viagra MOA

[Viagra]^® abbreviated prescribing information

Presentation- VIAGRA 50 or 100 mg film-coated tablets. Each tablet contains sildenafil citrate. Indication(s)- VIAGRA is indicated in adult men with erectile dysfunction which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. For VIAGRA to be effective sexual stimulation is required. Dosage and Administration- Use in adults- The recommended dose is 50 mg taken as needed approximately one hour before sexual activity. Based on efficacy and tolerability the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day. If VIAGRA is taken with food the onset of activity may be delayed compared to the fasted state. Elderly- Dosage adjustments are not required in elderly patients (≥ 65 years old). Renal impairment- The dosing recommendations described in “Use in adults” apply to patients with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min). Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min) a 25 mg dose should be considered. Based on efficacy and tolerability the dose may be increased stepwise to 50 mg up to 100 mg as necessary. Hepatic impairment- Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose should be considered. Based on efficacy and tolerability, the dose may be increased stepwise to 50 mg up to 100 mg as necessary. Paediatric population- VIAGRA is not indicated for individuals below 18 years of age. Use in patients taking other medicinal products- Except for ritonavir for which co- administration with sildenafil is not advised a starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors. In order to minimize the potential of developing postural hypotension in patients receiving alpha-blocker treatment patients should be stabilized on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of sildenafil at a dose of 25 mg should be considered. Method of administration- For oral use. Contraindications- Hypersensitivity to the active substance or to any of the excipients. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates and its co- administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated. The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension. Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure). VIAGRA is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: severe hepatic impairment, hypotension (blood pressure < 90/50 mmHg), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (minority of these patients have genetic disorders of retinal phosphodiesterase). Warning and Precautions- A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered. Cardiovascular risk factors- Prior to initiating any treatment for erectile dysfunction physicians should consider the cardiovascular status of their patients since there is a degree of cardiac risk associated 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. VIAGRA potentiates the hypotensive effect of nitrates. Serious cardiovascular events including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of VIAGRA. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of VIAGRA without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors. Priapism- Agents for the treatment of erectile dysfunction, including sildenafil, 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 anaemia, multiple myeloma or leukaemia). Prolonged Erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an erection that persists for 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. Fertility, pregnancy and lactation - VIAGRA is not indicated for use by women. There are no adequate and well-controlled studies in pregnant or breast-feeding women. No relevant adverse effects were found in reproduction studies in rats and rabbits following oral administration of sildenafil. There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers. Concomitant use with other PDE5 inhibitors or other treatments for erectile dysfunction- The safety and efficacy of combinations of sildenafil with other PDE5 inhibitors, or other pulmonary arterial hypertension (PAH) treatments containing sildenafil (REVATIO), or other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. Effects on vision- Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors. Patients should be advised that in the event of any sudden visual defect, they should stop taking VIAGRA and consult a physician immediately. Concomitant use with ritonavir is not advised. Concomitant use with alpha-blockers- Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing. 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 a dose of 25 mg should be considered. In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms. Effect on bleeding: Studies with human platelets indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore, sildenafil should be administered to these patients only after careful benefit-risk assessment. The film coating of the tablet contains lactose: VIAGRA should not be administered to men with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Women: VIAGRA is not indicated for use by women. Interactions- Effects of some other medicinal products on sildenafil- Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although no increased incidence of adverse events was observed in these patients, when sildenafil is administered concomitantly with CYP3A4 inhibitors, a starting dose of 25 mg should be considered. Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1,000% (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 administered alone. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is not advised and, in any event, the maximum dose of sildenafil should under no circumstances exceed 25 mg within 48 hours. Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a day) 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 and itraconazole would be expected to have greater effects. When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of sildenafil. 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. Therefore, concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma concentrations of sildenafil. Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to result in a serious interaction with sildenafil. Effects of sildenafil on other medicinal products: Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated. 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 light-headedness, but not syncope. No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg). Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dl. 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, showed no difference in the side effect profile in patients taking sildenafil compared to placebo treatment. In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone to healthy volunteers. Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. In healthy male volunteers, sildenafil at steady state (80 mg t.i.d.) resulted in a 49.8% increase in Bosentan AUC and a 42% increase in Bosentan Cmax (125 mg b.i.d.).

Effects on ability to drive and use machines –

VIAGRA may have a minor influence on the ability to drive and use machines. As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they react to VIAGRA, before driving or operating machinery. Overdosing- In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was 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. Adverse Reaction- The safety profile of VIAGRA is based on 9,570 patients in 74 double blind placebo-controlled clinical studies. The most commonly reported adverse reactions in clinical studies (≥1/10) were headache. While the commonly reported adverse reactions in clinical studies (≥ 1/100 and <1/10) were flushing, dyspepsia, nasal congestion, dizziness, nausea, hot flush, visual disturbance, cyanopsia and vision blurred. Pharmaceutical Precautions- Do not store above 25oC. Store in the original package in order to protect from moisture.

Abbreviated Prescribing Information

Presentation- Viagra^® sildenafil citrate, 50 mg orodispersible tablets, Blue, rounded, diamond-shaped tablets, marked “V50” on one side and plain on the other. Nature and contents of container Aluminum blisters in cartons of 2, 4 or 8 tablets. Not all pack sizes may be marketed Therapeutic indications: VIAGRA is indicated in adult men with erectile dysfunction, which is the inability to achieve or maintain a penile erection enough for satisfactory sexual performance. In order for VIAGRA to be effective, sexual stimulation is required Posology and method of administration: Use in adults Viagra should be taken as needed approximately one hour before sexual activity. The recommended dose is 50 mg taken on an empty stomach as concomitant intake with food delays absorption and delays the effect of the orodispersible tablet. Based on efficacy and tolerability the dose may be increased to 100 mg. The maximum recommended dose is 100 mg. For patients requiring a dose increase to 100 mg, two 50 mg orodispersible tablets should be administered sequentially. The maximum recommended dosing frequency is once per day. If a dose of 25 mg is required, the use of the 25 mg film-coated tablets should be recommended. Special populations, Elderly Dosage adjustments are not required in elderly patients (≥ 65 years old). Renal impairment the dosing recommendations described in ‘Use in adults’ apply to patients with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min). Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance <30 mL/min) a 25 mg dose should be considered. Based on efficacy and tolerability the dose may be increased stepwise to 50 mg up to 100 mg as necessary. Hepatic impairment Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose should be considered. Based on efficacy and tolerability, the dose may be increased stepwise to 50 mg up to 100 mg as necessary. Pediatric population VIAGRA is not indicated for individuals below 18 years of age. Use in patients taking other medicinal products except for ritonavir for which co-administration with sildenafil is not advised, a starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors. In order to minimize the potential of developing postural hypotension in patients receiving alpha-blocker treatment, patients should be stabilized on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of sildenafil at a dose of 25 mg should be considered Method of administration for oral use- The Orodispersible tablet should be placed in the mouth, on the tongue, and allowed to disintegrate before swallowing with or without water. It should be taken immediately upon removal from the blister. For patients requiring a second 50 mg orodispersible tablet to make a 100 mg dose, the second tablet should be taken upon full disintegration of the first tablet. There is a significant delay in absorption when orodispersible tablets are taken with a high fat meal compared to the fasted state. It is recommended that orodispersible tablets be taken on an empty stomach. Orodispersible tablets can be taken with or without water. Contraindications- Hypersensitivity to the active substance or to any of the excipients listed. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated. The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure). VIAGRA is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: severe hepatic impairment, hypotension (blood pressure <90/50 mmH recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterase’s). Warnings and Precautions- A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered. Cardiovascular risk factors Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. 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. VIAGRA potentiates the hypotensive effect of nitrates. Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of VIAGRA. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of VIAGRA without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors. Priapism Agents for the treatment of erectile dysfunction, including sildenafil, 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). Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. 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. Concomitant use with other PDE5 inhibitors or other treatments for erectile dysfunction -the safety and efficacy of combinations of sildenafil with other PDE5 Inhibitors, or other pulmonary arterial hypertension (PAH) treatments containing sildenafil (REVATIO), or other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. Effects on vision Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors (see section 4.8). Patients should be advised that in the event of any sudden visual defect, they should stop taking VIAGRA and consult a physician immediately. Concomitant use with ritonavir Co-administration of sildenafil with ritonavir is not advised. Concomitant use with alpha-blockers Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing. 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 a dose of 25 mg should be considered (see section 4.2). In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms. Effect on bleeding Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these patients only after careful benefit-risk assessment. In Women VIAGRA is not indicated for use by women. Pregnancy and lactation- VIAGRA is not indicated for use by women. There are no adequate and well-controlled studies in pregnant or breast-feeding women. No relevant adverse effects were found in reproduction studies in rats and rabbits following oral administration of sildenafil. There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers Interactions- Effects of other medicinal products on sildenafil 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 and inducers of these isoenzymes may increase sildenafil clearance. In vivo studies Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although no increased incidence of adverse events was observed in these patients, when sildenafil is administered concomitantly with CYP3A4 inhibitors, a starting dose of 25 mg should be considered, Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component, it has the potential to result in a serious interaction with sildenafil. Effects of sildenafil on other medicinal products In vitro studies Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes. There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole. In vivo studies Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated ,Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favorable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing. 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, 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 light-headedness, but not syncope. No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg). Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dl. 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, showed no difference in the side effect profile in patients taking sildenafil compared to placebo treatment. In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone to healthy volunteers. Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. In healthy male volunteers, sildenafil at steady state (80 mg t.i.d.) resulted in a 49.8% increase in Bosentan AUC and a 42% increase in Bosentan Cmax (125 mg b.i.d.). Effects on ability to drive and use machines- Viagra may have a minor influence on the ability to drive and use machines. As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they react to VIAGRA, before driving or operating machinery Overdosing- In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was 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. Adverse Events: The safety profile of VIAGRA is based on 9,570 patients in 74 double-blind placebo-controlled clinical studies. The most reported adverse reactions in clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, nasal congestion, dizziness, nausea, hot flush, visual disturbance, cyanopsia and vision blurred. Pharmaceutical precautions: Shelf life, Do not use VIAGRA orodispersible tablets after the expiry date which is stated on the carton / Blister label after EXP- The expiry date refers to the last day of the 36 months., Special precautions for storage, Keep out of the sight and reach of children. Do not store above 30 °C, Store in the original package in order to protect from moisture. Reference- Viagra [package insert]. Fareva Amboise Zone Industrielle 29 route des Industries 37530 Pocé-sur-Cisse France: Pfizer;May 2019.

Date of the document- Dec 2020, Full prescribing information is available upon request

Contraindications:

Hypersensitivity to the active substance or to any of the excipients listed in section. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated. The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension. Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure). VIAGRA is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: severe hepatic impairment, hypotension (blood pressure <90/50 mmHg), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

Special warnings and precautions for use

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and

determine potential underlying causes, before pharmacological treatment is considered.

Cardiovascular risk factors

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. 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. VIAGRA potentiates the hypotensive effect of nitrates. Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of VIAGRA. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of VIAGRA without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors.

Priapism

Agents for the treatment of erectile dysfunction, including sildenafil, 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 anaemia, multiple myeloma or leukaemia).
Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. 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.

Concomitant use with other PDE5 inhibitors or other treatments for erectile dysfunction

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

Effects on vision

Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors. Patients should be advised that in the event of any sudden visual defect, they should stop taking VIAGRA and consult a physician immediatey.

Concomitant use with ritonavir

Co-administration of sildenafil with ritonavir is not advised.

Concomitant use with alpha-blockers

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing. In order to minimise the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at a dose of 25 mg should be considered. In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.

Effect on bleeding

Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these patients only after careful benefit-risk assessment.

Women

VIAGRA is not indicated for use by women.

Undesirable effects

The safety profile of VIAGRA is based on 9,570 patients in 74 double-blind placebo-controlled clinical studies. The most commonly reported adverse reactions in clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, nasal congestion, dizziness, nausea, hot flush, visual disturbance, cyanopsia and vision blurred.