sildenafil: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Revatio

4.1 Therapeutic indications

Applies to: Revatio 20 mg film-coated tablets · Revatio 10 mg/ml powder for oral suspension

Adults
Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.

Paediatric population
Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension.
Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease (see section 5.1).

Applies to: Revatio 0.8 mg/ml solution for injection

Revatio solution for injection is for the treatment of adult patients (≥ 18 years) with pulmonary arterial hypertension who are currently prescribed oral Revatio and who are temporarily unable to take oral therapy, but are otherwise clinically and haemodynamically stable.

Revatio (oral) is indicated for treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.

4.2 Posology and method of administration

Applies to: Revatio 20 mg film-coated tablets

Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. In case of clinical deterioration in spite of Revatio treatment, alternative therapies should be considered.

Posology

Adults
The recommended dose is 20 mg three times a day (TID). Physicians should advise patients who forget to take Revatio to take a dose as soon as possible and then continue with the normal dose.
Patients should not take a double dose to compensate for the missed dose.

Paediatric population (1 year to 17 years)
For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is 10 mg three times a day and for patients > 20 kg is 20 mg three times a day. Higher than recommended doses should not be used in paediatric patients with PAH (see also sections 4.4 and 5.1). The 20 mg tablet should not be used in cases where 10 mg TID should be administered in younger patients. Other pharmaceutical forms are available for administration to patients ≤ 20 kg and other younger patients who are not able to swallow tablets.

Patients using other medicinal products
In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A downward dose adjustment to 20 mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone. For the use of sildenafil with the most potent CYP3A4 inhibitors, see section 4.3. Dose adjustments for sildenafil may be required when co-administered with CYP3A4 inducers (see section 4.5).

Special populations

Elderly (≥ 65 years)
Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients.

Renal impairment
Initial dose adjustments are not required in patients with renal impairment, including severe renal impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

Hepatic impairment
Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and B). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3).

Paediatric population (children less than 1 year and neonates)
Outside its authorised indications, sildenafil should not be used in neonates with persistent pulmonary hypertension of the newborn as risks outweigh the benefits (see section 5.1). The safety and efficacy of Revatio in other conditions in children below 1 year of age has not been established. No data are available.

Discontinuation of treatment
Limited data suggest that the abrupt discontinuation of Revatio is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified monitoring is recommended during the discontinuation period.

Method of administration
Revatio is for oral use only. Tablets should be taken approximately 6 to 8 hours apart with or without food.

Applies to: Revatio 0.8 mg/ml solution for injection

Revatio solution for injection should be administered to patients already prescribed oral Revatio as a replacement for oral administration under conditions where they are temporarily unable to take oral Revatio therapy.

Safety and effectiveness of doses higher than 12.5 ml (10 mg) TID have not been established.

Posology

Adults
The recommended dose is 10 mg (corresponding to 12.5 ml) three times a day administered as an intravenous bolus injection (see section 6.6).

A 10 mg dose of Revatio solution for injection is predicted to provide exposure of sildenafil and its N-desmethyl metabolite and pharmacological effects comparable to those of a 20 mg oral dose.

Patients using other medicinal products
In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A downward dose adjustment to 10 mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A

downward dose adjustment to 10 mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone. For the use of sildenafil with the most potent CYP3A4 inhibitors, see section 4.3. Dose adjustments for sildenafil may be required when co-administered with CYP3A4 inducers (see section 4.5).

Special populations

Elderly (≥ 65 years)
Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients.

Renal impairment
Initial dose adjustments are not required in patients with renal impairment, including severe renal impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 10 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

Hepatic impairment
Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and B). A downward dose adjustment to 10 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3).

Paediatric population
Revatio solution for injection is not recommended for use in children below 18 years due to insufficient data on safety and efficacy. Outside its authorised indications, sildenafil should not be used in neonates with persistent pulmonary hypertension of the newborn as risks outweigh the benefits (see section 5.1).

Discontinuation of treatment
Limited data suggest that the abrupt discontinuation of oral Revatio is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified monitoring is recommended during the discontinuation period.

Method of administration
Revatio solution for injection is for intravenous use as a bolus injection.
See section 6.6 for instructions of use.

Applies to: Revatio 10 mg/ml powder for oral suspension

Posology

Paediatric population (1 year to 17 years)
For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is 10 mg (1 ml of reconstituted suspension) three times a day and for patients > 20 kg is 20 mg (2 ml of reconstituted suspension) three times a day. Higher than recommended doses should not be used in paediatric patients with PAH (see also sections 4.4 and 5.1).

Special populations

Elderly (≥ 65 years)
Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients.

Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C), (see section 4.3).

Method of administration
Revatio powder for oral suspension is for oral use only. The reconstituted oral suspension (a white, grape flavoured oral suspension) should be taken approximately 6 to 8 hours apart with or without food.

Before withdrawing the required dose, shake the bottle vigorously for a minimum of 10 seconds.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Applies to: Revatio 20 mg film-coated tablets · Revatio 10 mg/ml powder for oral suspension

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form due to the hypotensive effects of nitrates (see section 5.1).

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 (see section 4.5).
Combination with the most potent of the CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir) (see section 4.5).

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 (see section 4.4).

The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated:
Severe hepatic impairment,
Recent history of stroke or myocardial infarction,
Severe hypotension (blood pressure < 90/50 mmHg) at initiation.

Applies to: Revatio 0.8 mg/ml solution for injection

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form due to the hypotensive effects of nitrates (see section 5.1).

Combination with the most potent of the CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir) (see section 4.5).

The safety of sildenafil has not been studied in the following sub-groups of patients, and its use is therefore contraindicated:
Severe hepatic impairment,
Recent history of stroke or myocardial infarction,
Severe hypotension (blood pressure < 90/50 mmHg) at initiation.

4.8 Undesirable effects

Applies to: Revatio 20 mg film-coated tablets

Summary of the safety profile
In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg TID doses of Revatio and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID was 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the 277 subjects treated in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day (4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 % of 183 patients on study treatment were receiving Revatio 80 mg TID.

In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day, as tolerated) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68 % of 133 patients on study treatment were receiving Revatio 80 mg TID.

In the two placebo-controlled studies adverse events were generally mild to moderate in severity. The most commonly reported adverse reactions that occurred (greater or equal to 10 %) on Revatio compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.

In a study to assess the effects of different dose levels of sildenafil the safety data for sildenafil 20 mg TID (recommended dose) and for sildenafil 80 mg TID (4 times the recommended dose), were consistent with the established safety profile of sildenafil in previous adult PAH studies.

Tabulated list of adverse reactions
Adverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 % difference) on Revatio in the pivotal study or in the Revatio combined data set of both the placebo-controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg TID are listed in Table 1 below by class and frequency grouping (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Reports from post-marketing experience are included in italics.

Table 1: Adverse reactions from sildenafil placebo-controlled studies in PAH and post-marketing experience in adults

MedDRA system organ class (V.14.0)
Adverse reaction
Infections and infestations
Common

cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis
Blood and lymphatic system disorders
Common anaemia
Metabolism and nutrition disorders

Common fluid retention
Psychiatric disorders
Common insomnia, anxiety
Nervous system disorders
Very common headache
Common migraine, tremor, paraesthesia, burning sensation, hypoaesthesia
Eye disorders
Common retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia Uncommon visual acuity reduced, diplopia, abnormal sensation in eye Not known Non-arteritic anterior ischaemic optic neuropathy (NAION)*, Retinal vascular occlusion*, Visual field defect* Ear and labyrinth disorders Common vertigo Not known sudden hearing loss Vascular disorders Very common flushing Not Known hypotension Respiratory, thoracic and mediastinal disorders Common epistaxis, cough, nasal congestion

Gastrointestinal disorders
Very common diarrhoea, dyspepsia
Common gastritis, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth Skin and subcutaneous tissue disorders

Common alopecia, erythema, night sweats
Not known rash
Musculoskeletal and connective tissue disorders

Very common pain in extremity
Common myalgia, back pain
Renal and urinary disorders

Uncommon haematuria
Reproductive system and breast disorders
Uncommon penile haemorrhage, haematospermia, gynaecomastia
Not known priapism, erection increased
General disorders and administration site conditions

Common pyrexia
*These adverse events/reactions have been reported in patients taking sildenafil for the treatment of male erectile dysfunction (MED).

Paediatric population
In the placebo-controlled study of Revatio in patients 1 to 17 years of age with pulmonary arterial hypertension, a total of 174 patients were treated three times a day with either low (10 mg in patients > 20 kg; no patients ≤ 20 kg received the low dose), medium (10 mg in patients ≥ 8-20 kg; 20 mg in patients ≥ 20-45 kg; 40 mg in patients > 45 kg) or high dose (20 mg in patients ≥ 8-20 kg; 40 mg in patients ≥ 20-45 kg; 80 mg in patients > 45 kg) regimens of Revatio and 60 were treated with placebo.

The adverse reactions profile seen in this paediatric study was generally consistent with that in adults (see table above). The most common adverse reactions that occurred (with a frequency ≥ 1 %) in Revatio patients (combined doses) and with a frequency > 1 % over placebo patients were pyrexia, upper respiratory tract infection (each 11.5%), vomiting (10.9%), erection increased (including spontaneous penile erections in male subjects) (9.0%), nausea, bronchitis (each 4.6%), pharyngitis (4.0%), rhinorrhoea (3.4%), and pneumonia, rhinitis (each 2.9%).

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered the long-term extension study. Subjects on active sildenafil therapy continued on the same treatment regimen, while those in the placebo group in the short-term study were randomly reassigned to sildenafil treatment.

The most common adverse reactions reported across the duration of the short-term and long-term studies were generally similar to those observed in the short-term study. Adverse reactions reported in >10% of 229 subjects treated with sildenafil (combined dose group, including 9 patients that did not continue into the long-term study) were upper respiratory infection (31%), headache (26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), pyrexia (17%), diarrhoea (15%), and influenza, epistaxis (12% each). Most of these adverse reactions were considered mild to moderate in severity.

Serious adverse events were reported in 94 (41%) of the 229 subjects receiving sildenafil. Of the 94 subjects reporting a serious adverse event, 14/55 (25.5%) subjects were in the low dose group, 35/74 (47.3%) in the medium dose group, and 45/100 (45%) in the high dose group. The most common serious adverse events that occurred with a frequency ≥ 1 % in sildenafil patients (combined doses) were pneumonia (7.4%), cardiac failure, pulmonary hypertension (each 5.2%), upper respiratory tract infection (3.1%), right ventricular failure, gastroenteritis (each 2.6%), syncope, bronchitis, bronchopneumonia, pulmonary arterial hypertension (each 2.2%), chest pain, dental caries (each 1.7%), and cardiogenic shock, gastroenteritis viral, urinary tract infection (each 1.3%).

The following serious adverse events were considered to be treatment related, enterocolitis, convulsion, hypersensitivity, stridor, hypoxia, neurosensory deafness and ventricular arrhythmia.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Applies to: Revatio 0.8 mg/ml solution for injection

Adverse reactions that resulted from intravenous Revatio use are similar to those associated with oral Revatio use. Since there are limited data for intravenous Revatio use and since pharmacokinetic models predict that 20 mg oral and 10 mg intravenous formulations will yield similar plasma exposures, the safety information for intravenous Revatio is supported by that of oral Revatio.

Intravenous administration
A 10 mg dose of Revatio solution for injection is predicted to provide total exposure of free sildenafil and its N-desmethyl metabolite and their combined pharmacological effects comparable to those of a 20 mg oral dose.

Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability and pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus injection to patients with Pulmonary Arterial Hypertension (PAH) who were already receiving and stable on oral Revatio 20 mg three times per day.

A total of 10 PAH subjects enrolled and completed the study. The mean postural changes in systolic and diastolic blood pressure over time were small (< 10 mmHg) and returned towards baseline beyond 2 hours. No symptoms of hypotension were associated with these changes. The mean changes in heart rate were clinically insignificant. Two subjects experienced a total of 3 adverse reactions (flushing, flatulence and hot flush). There was one serious adverse reaction in a subject with severe ischaemic

cardiomyopathy who experienced ventricular fibrillation and death 6 days post study. It was judged to be unrelated to the study medicinal product.

Oral administration
In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were randomized to and treated with 20 mg, 40 mg or 80 mg TID doses of oral Revatio and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID was 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the 277 subjects treated in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day (4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 % of 183 patients on study treatment were receiving Revatio 80 mg TID.

In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with oral Revatio (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse drug reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known adverse events headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68 % of 133 patients on study treatment were receiving Revatio 80 mg TID.

In the two placebo-controlled oral Revatio studies adverse events were generally mild to moderate in severity. The most commonly reported adverse reactions that occurred (greater or equal to 10 %) on Revatio compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.

Tabulated list of adverse reactions
Adverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 % difference) on Revatio in the pivotal study or in the Revatio combined data set of both the placebo-controlled studies in pulmonary arterial hypertension, at oral doses of 20, 40 or 80 mg TID are listed in Table 1 below by class and frequency grouping (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to ≤ 1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Reports from post-marketing experience are included in italics.

Table 1: Adverse reactions from sildenafil placebo-controlled studies in PAH and post-marketing experience in adults

MedDRA system organ class (V.14.0)
Adverse reaction
Infections and infestations
Common cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis
Blood and lymphatic system disorders
Common anaemia

Metabolism and nutrition disorders
Common fluid retention
Psychiatric disorders

Common insomnia, anxiety
Nervous system disorders
Very common headache
Common migraine, tremor, paraesthesia, burning sensation, hypoaesthesia
Eye disorders

Common retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia Uncommon visual acuity reduced, diplopia, abnormal sensation in eye Not known Non-arteritic anterior ischaemic optic neuropathy (NAION)*, Retinal vascular occlusion*, Visual field defect* Ear and labyrinth disorders Common vertigo Not known sudden hearing loss Vascular disorders Very common flushing Not Known hypotension Respiratory, thoracic and mediastinal disorders Common epistaxis, cough, nasal congestion Gastrointestinal disorders Very common diarrhoea, dyspepsia Common gastritis, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth Skin and subcutaneous tissue disorders

Common alopecia, erythema, night sweats
Not known rash
Musculoskeletal and connective tissue disorders

Very common pain in extremity
Common myalgia, back pain
Renal and urinary disorders

Common pyrexia
*These adverse events/reactions have been reported in patients taking sildenafil in the treatment of male erectile dysfunction (MED).

Applies to: Revatio 10 mg/ml powder for oral suspension

In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68 % of 133 patients on study treatment were receiving Revatio 80 mg TID.

Tabulated list of adverse reactions
Adverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 % difference) on Revatio in the pivotal study or in the Revatio combined data set of both the placebo-controlled studies in pulmonary arterial hypertension,, at doses of 20, 40 or 80 mg TID are listed in Table 1 below by class and frequency grouping (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Reports from post-marketing experience are included in italics.

Table 1: Adverse reactions from sildenafil placebo-controlled studies in PAH and post-marketing experience in adults

MedDRA system organ class (V.14.0)
Adverse reaction
Infections and infestations

Common cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis
Blood and lymphatic system disorders

Common anaemia
Metabolism and nutrition disorders
Common fluid retention
Psychiatric disorders
Common insomnia, anxiety
Nervous system disorders

Very common headache
Common migraine, tremor, paraesthesia, burning sensation, hypoaesthesia
Eye disorders
Common retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia

Uncommon visual acuity reduced, diplopia, abnormal sensation in eye
Not known
Non-arteritic anterior ischaemic optic neuropathy (NAION)*, Retinal vascular occlusion*, Visual field defect* Ear and labyrinth disorders Common vertigo Not known sudden hearing loss Vascular disorders Very common flushing Not known hypotension Respiratory, thoracic and mediastinal disorders Common epistaxis, cough, nasal congestion Gastrointestinal disorders

Very common diarrhoea, dyspepsia
Common gastritis, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth Skin and subcutaneous tissue disorders Common alopecia, erythema, night sweats Not known rash Musculoskeletal and connective tissue disorders Very common pain in extremity Common myalgia, back pain Renal and urinary disorders Uncommon haematuria Reproductive system and breast disorders Uncommon penile haemorrhage, haematospermia, gynaecomastia Not known priapism, erection increased General disorders and administration site conditions

Common pyrexia
*These adverse events/reactions have been reported in patients taking sildenafil for the treatment of male erectile dysfunction (MED).

The following serious adverse events were considered to be treatment related, enterocolitis, convulsion, hypersensitivity, stridor, hypoxia, neurosensory deafness and ventricular arrhythmia.

4.4 Special warnings and precautions for use

Applies to: Revatio 20 mg film-coated tablets

The efficacy of Revatio has not been established in patients with severe pulmonary arterial hypertension (functional class IV). If the clinical situation deteriorates, therapies that are recommended at the severe stage of the disease (eg, epoprostenol) should be considered (see section 4.2). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO functional class I pulmonary arterial hypertension.

Studies with sildenafil have been performed in forms of pulmonary arterial hypertension related to primary (idiopathic), connective tissue disease associated or congenital heart disease associated forms of PAH (see section 5.1). The use of sildenafil in other forms of PAH is not recommended.

In the long term paediatric extension study, an increase in deaths was observed in patients administered doses higher than the recommended dose. Therefore, doses higher than the recommended doses should not be used in paediatric patients with PAH (see also sections 4.2 and 5.1).

Retinitis pigmentosa
The safety of sildenafil has not been studied in patients with known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases) and therefore its use is not recommended.

Vasodilatory action
When prescribing sildenafil, physicians should carefully consider whether patients with certain underlying conditions could be adversely affected by sildenafil’s mild to moderate vasodilatory effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction (see section 4.4).

Cardiovascular risk factors
In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported in temporal association with the use of sildenafil. 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 sildenafil without sexual activity.
It is not possible to determine whether these events are related directly to these factors or to other factors.

Priapism
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 (see section 4.8).

Vaso-occlusive crises in patients with sickle cell anaemia
Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported more commonly by patients receiving Revatio than those receiving placebo leading to the premature termination of this study.

Visual events
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 (see section 4.8). In the event of any sudden visual defect, the treatment should be stopped immediately and alternative treatment should be considered (see section 4.3).

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 susceptible individuals (see section 4.5). In order to minimise the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms.

Bleeding disorders
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.

Vitamin K antagonists
In pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients with pulmonary arterial hypertension secondary to connective tissue disease.

Veno-occlusive disease
No data are available with sildenafil in patients with pulmonary hypertension associated with pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.

Excipient information
Lactose monohydrate is present in the tablet film coat. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Revatio 20 mg film-coated tablets contain less than 1 mmol sodium (23 mg) per tablet. Patients on low sodium diets can be informed that this medicinal product is essentially ‘sodium-free’.

Use of sildenafil with bosentan
The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.5 and 5.1).

Concomitant use with other PDE5 inhibitors
The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, including Viagra, has not been studied in PAH patients and such concomitant use is not recommended (see section 4.5).

Applies to: Revatio 0.8 mg/ml solution for injection

No clinical data is available for sildenafil IV administration in patients who are clinically or haemodynamically unstable. Its use is accordingly not recommended in these patients.

The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO functional class I pulmonary arterial hypertension.

Use of sildenafil with bosentan
The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.5 and 5.1).

Applies to: Revatio 10 mg/ml powder for oral suspension

Excipient information
Revatio 10 mg/ml powder for oral suspension contains sorbitol, which is a source of fructose. Patients with rare hereditary fructose intolerance (HFI) should not take this medicinal product.

Revatio 10 mg/ml powder for oral suspension contains 1 mg sodium benzoate per ml of reconstituted oral suspension. Benzoates may increase unconjugated bilirubin levels by displacing bilirubin from albumin, which may increase neonatal jaundice. Neonatal hyperbilirubinaemia may lead to kernicterus (non-conjugated bilirubin deposits in the brain tissue) and encephalopathy.

Revatio 10 mg/ml powder for oral suspension contains less than 1 mmol sodium (23 mg) per ml of reconstituted oral suspension. Patients on low sodium diets can be informed that this medicinal product is essentially ‘sodium-free’.

Use of sildenafil with bosentan
The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.5 and 5.1).

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: Revatio 20 mg film-coated tablets · Revatio 10 mg/ml powder for oral suspension

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. For dose recommendations, see sections 4.2 and 4.3.

In vivo studies
Co-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections 4.8 and 5.1).

The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg, ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients (see section 4.4).

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, ketoconazole, itraconazole, ritonavir).

CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with CYP3A4 inducer bosentan.

Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 125 mg twice daily with sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63 % decrease of sildenafil AUC. A population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials including a 12 week study to assess the efficacy and safety of oral sildenafil 20 mg three times a day when added to a stable dose of bosentan (62.5 mg – 125 mg twice a day) indicated a decrease in sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see sections 4.4 and 5.1).

Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine.

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. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).

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. For dose recommendations, see section 4.2.

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). For dose recommendations, see section 4.2. 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 principal circulating metabolite.
No dose adjustment is required. 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 sildenafil (50 mg) to healthy volunteers. No dose adjustment is required.

The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. Therefore dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).

The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that co-administration of beta-blockers in combination with CYP3A4 substrates might result in an additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use of sildenafil and grapefruit juice is not recommended.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.

Co-administration of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg) did not affect the pharmacokinetics of sildenafil.

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with sildenafil (see section 4.3).

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).

There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies
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 had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.

No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol.

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.

In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50 % increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from a study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) indicated an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with co-administration of steady-state sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1).

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.

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 systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, 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 lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 4.4).

Sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.

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 (see section 4.3).

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 favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).

Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg).

Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil is initiated in patients treated with sacubitril/valsartan.

Paediatric population
Interaction studies have only been performed in adults.

Applies to: Revatio 0.8 mg/ml solution for injection

Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using oral sildenafil. These results are relevant to other populations and routes of administration.

Effects of other medicinal products on intravenous sildenafil
Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4 inhibitors should be less than observed after oral sildenafil administration. The magnitude of the interaction is expected to be reduced for intravenous sildenafil, as interactions for oral sildenafil are due, at least in part, to effects on oral first pass metabolism.

Effects of other medicinal products on oral sildenafil

In vivo studies
Co-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections 4.8 and 5.1).

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients (see section 4.4).

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on oral sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at an oral dose of 80 mg three times a day compared to the exposure at an oral dose of 20 mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, ketoconazole, itraconazole, ritonavir).

CYP3A4 inducers seemed to have a substantial impact on the oral pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with CYP3A4 inducer bosentan.

Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 125 mg twice daily with oral sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63 % decrease of sildenafil AUC. A population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials including a 12 week study to assess the efficacy and safety of oral sildenafil 20 mg three times a day when added to a stable dose of bosentan (62.5 mg – 125 mg twice a day) indicated a decrease in sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see sections 4.4 and 5.1).

Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine.

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) with oral 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. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a day) with oral 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. For dose recommendations, see section 4.2.

When a single 100 mg dose of oral 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). For dose recommendations, see section 4.2. 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 oral sildenafil or its principal circulating metabolite. No dose adjustment is required. 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 oral sildenafil (50 mg) to healthy volunteers. No dose adjustment is required.

The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone) are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors like saquinavir or erythromycin), a seven-fold increase in exposure is assumed. Therefore dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).

The population pharmacokinetic analysis in pulmonary arterial hypertension patients receiving oral sildenafil suggested that co-administration of beta-blockers in combination with CYP3A4 substrates might result in an additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of oral sildenafil. No dose adjustment is required but the concomitant use of sildenafil and grapefruit juice is not recommended.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the oral bioavailability of sildenafil.

Co-administration of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg) did not affect the oral pharmacokinetics of sildenafil.

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with sildenafil (see section 4.3).

Effects of oral 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).

There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies
No significant interactions were shown when oral sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.

Oral sildenafil had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.

No interactions were observed between sildenafil (100 mg single oral dose) and acenocoumarol.

Oral sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg).

Oral sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dl.

In a study of healthy volunteers oral sildenafil at steady state (80 mg three times a day) resulted in a 50 % increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from a study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) indicated an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with co-administration of steady-state sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1).

In a specific interaction study, where oral 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.

In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and oral 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 systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, 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 lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 4.4).

Sildenafil (100 mg single oral dose) did not affect the steady state pharmacokinetics of the HIV protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.

Oral sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg).

Paediatric population
Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Applies to: Revatio 20 mg film-coated tablets · Revatio 0.8 mg/ml solution for injection · Revatio 10 mg/ml powder for oral suspension

Women of childbearing potential and contraception in males and females
Due to lack of data on effects of Revatio in pregnant women, Revatio is not recommended for women of childbearing potential unless also using appropriate contraceptive measures.

Pregnancy
There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy and embryonal/foetal development. Studies in animals have shown toxicity with respect to postnatal development (see section 5.3).

Due to lack of data, Revatio should not be used in pregnant women unless strictly necessary.

Breast-feeding
There are no adequate and well controlled studies in lactating women. Data from one lactating woman indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk at very low levels. No clinical data are available regarding adverse events in breast-fed infants, but amounts ingested would not be expected to cause any adverse effects. Prescribers should carefully assess the mother’s clinical need for sildenafil and any potential adverse effects on the breast-fed child.

Fertility
Non-clinical data revealed no special hazard for humans based on conventional studies of fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Applies to: Revatio 20 mg film-coated tablets · Revatio 0.8 mg/ml solution for injection · Revatio 10 mg/ml powder for oral suspension

Revatio has moderate 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 might be affected by Revatio, before driving or using machines.

4.9 Overdose

Applies to: Revatio 20 mg film-coated tablets · Revatio 10 mg/ml powder for oral suspension

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. At single doses of 200 mg the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, and 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.

5.
PHARMACOLOGICAL PROPERTIES

Applies to: Revatio 0.8 mg/ml solution for injection

In single dose volunteer studies of oral doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. At single oral doses of 200 mg the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, and altered vision) was increased.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Revatio 20 mg film-coated tablets

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC code: G04BE03

Mechanism of action
Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart from the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Pharmacodynamic effects
Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. 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 causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen.
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported.

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean

resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Revatio 0.8 mg/ml solution for injection

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC code: G04BE03

Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic oral dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic oral dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended oral dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen.

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Revatio 10 mg/ml powder for oral suspension

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC code: G04BE03

Pharmacodynamic effects
Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. 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 causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mm Hg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mm Hg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen.

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported.
In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: Revatio 20 mg film-coated tablets

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 oral bioavailability is 41 % (range 25-63 %). After oral three times a day dosing of sildenafil, AUC and Cmax increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg three times a day a more than dose proportional increase in sildenafil plasma levels has been observed. In pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg three times a day was on average 43 % (90 % CI: 27 % - 60 %) higher compared to the lower doses.

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29 % however, the extent of absorption was not significantly affected (AUC decreased by 11 %).

Distribution
The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N-desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding is independent of total drug concentrations.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Revatio 0.8 mg/ml solution for injection

Absorption
The mean absolute oral bioavailability for sildenafil is 41 % (range 25-63 %). In study A1481262 Cmax, CL and AUC (0-8) of 248 ng/ml, 30.3 l/h and 330 ng h/ml, were observed respectively. The Cmax and AUC (0-8) of the N-desmethyl metabolite were 30.8 ng/ml and 147 ng h/ml, respectively.

Distribution
The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N- desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding is independent of total drug concentrations.

Biotransformation
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.
This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50 % that of the parent drug. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those of sildenafil after 20 mg three times a day oral dosing (translating into a 36 % contribution to sildenafil’s pharmacological effects). The subsequent effect on efficacy is unknown. In healthy volunteers, the plasma levels of the N-desmethyl metabolite following intravenous dosing are significantly lower than those observed following oral dosing. At steady state plasma concentrations of N-desmethyl metabolite are approximately 16 % versus 61 % those of sildenafil after IV and oral dosing, respectively.

Elimination

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Revatio 10 mg/ml powder for oral suspension

Distribution
The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N- desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding is independent of total drug concentrations.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Viagra

4.1 Therapeutic indications

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets · VIAGRA 50 mg orodispersible tablets · VIAGRA 50 mg orodispersible films

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.

In order for VIAGRA to be effective, sexual stimulation is required.

4.2 Posology and method of administration

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets

Posology

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 (see section 5.2).

Special populations

Elderly
Dose 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 step-wise 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 step-wise 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
With the exception of ritonavir for which co-administration with sildenafil is not advised (see section 4.4) a starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors (see section 4.5).

In order to minimise the potential of developing postural hypotension in patients receiving alpha-blocker treatment, patients should be stabilised on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of sildenafil at a dose of 25 mg should be considered (see sections 4.4 and 4.5).

Method of administration

For oral use.

Applies to: VIAGRA 50 mg orodispersible tablets

Posology

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 (see section 5.2).

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
Dose 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 step-wise 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
With the exception of ritonavir for which co-administration with sildenafil is not advised (see section 4.4), a starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors (see section 4.5).

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 (see section 5.2). It is recommended that orodispersible tablets be taken on an empty stomach. Orodispersible tablets can be taken with or without water.

Applies to: VIAGRA 50 mg orodispersible films

Posology

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 film (see section 5.2).

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 films 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
Dose 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 step-wise to 50 mg up to 100 mg as necessary.

Paediatric population
VIAGRA is not indicated for individuals below 18 years of age.

Method of administration

For oral use.

The aluminium pouch should be carefully peeled open (and not cut open). The orodispersible film should be taken out with a dry finger, placed on the tongue and allowed to disintegrate with or without water. During disintegration saliva may be swallowed, but without swallowing the film. It should be taken immediately upon removal from the pouch.

For patients requiring a second 50 mg orodispersible film to make a 100 mg dose, the second film should be taken upon full disintegration of the first film.

A significant delay in absorption is expected when orodispersible films are taken with a high fat meal compared to the fasted state (see section 5.2). It is recommended that orodispersible films be taken on an empty stomach. Orodispersible films can be taken with or without water.

4.3 Contraindications

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets · VIAGRA 50 mg orodispersible films

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway (see section 5.1), 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.

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 (see section 4.4).

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).

Applies to: VIAGRA 50 mg orodispersible tablets

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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).

4.8 Undesirable effects

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets

Summary of the safety profile

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.

Adverse reactions from post-marketing surveillance has been gathered covering an estimated period > 10 years. Because not all adverse reactions are reported to the Marketing Authorisation Holder and included in the safety database, the frequencies of these reactions cannot be reliably determined.

Tabulated list of adverse reactions

In the table below all medically important adverse reactions, which occurred in clinical studies at an incidence greater than placebo are listed by system organ class and frequency (very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Medically important adverse reactions reported at an incidence greater than placebo in controlled clinical studies and medically important adverse reactions reported through post-marketing surveillance

System Organ
Class
Very common
(≥ 1/10)
Common
(≥ 1/100 and
<1/10)
Uncommon
(≥ 1/1 000 and
<1/100)
Rare (≥ 1/10 000 and
<1/1 000)
Infections and infestations

Rhinitis

Immune system disorders

Hypersensitivity

Nervous system disorders
Headache
Dizziness
Somnolence,
Hypoaesthesia
Cerebrovascular accident,
Transient ischaemic attack, Seizure,* Seizure recurrence,* Syncope
Eye disorders

Visual colour distortions**,
Visual disturbance,
Vision blurred
Lacrimation disorders***, Eye pain, Photophobia,
Photopsia, Ocular hyperaemia, Visual brightness,
Conjunctivitis
Non-arteritic anterior ischaemic optic neuropathy (NAION)*,
Retinal vascular occlusion*, Retinal haemorrhage,
Arteriosclerotic retinopathy, Retinal disorder, Glaucoma,
Visual field defect,
Diplopia, Visual acuity reduced, Myopia,
Asthenopia, Vitreous floaters, Iris disorder,
Mydriasis, Halo vision,
Eye oedema, Eye swelling,
Eye disorder, Conjunctival hyperaemia, Eye irritation,
Abnormal sensation in eye, Eyelid oedema,
Scleral discoloration
Ear and labyrinth disorders

Vertigo, Tinnitus
Deafness
Cardiac disorders

Tachycardia,
Palpitations
Sudden cardiac death*,
Myocardial infarction,
Ventricular arrhythmia*,
Atrial fibrillation,
Unstable angina
Vascular disorders

Flushing, Hot flush
Hypertension,
Hypotension

Respiratory, thoracic and mediastinal disorders

Nasal congestion
Epistaxis, Sinus congestion
Throat tightness, Nasal oedema, Nasal dryness

System Organ
Class
Very common
(≥ 1/10)
Common
(≥ 1/100 and
<1/10)
Uncommon
(≥ 1/1 000 and
<1/100)
Rare (≥ 1/10 000 and
<1/1 000)
Gastrointestinal disorders

Nausea,
Dyspepsia
Gastro oesophagael reflux disease,
Vomiting,
Abdominal pain upper, Dry mouth
Hypoaesthesia oral
Skin and subcutaneous tissue disorders

Rash
Stevens-Johnson
Syndrome (SJS)*, Toxic
Epidermal Necrolysis
(TEN)*
Musculoskeletal and connective tissue disorders

Myalgia, Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Penile haemorrhage,
Priapism*,
Haematospermia, Erection increased
General disorders and administration site conditions

Chest pain, Fatigue,
Feeling hot
Irritability
Investigations

Heart rate increased

*Reported during post-marketing surveillance only
**Visual colour distortions: Chloropsia, Chromatopsia, Cyanopsia, Erythropsia and Xanthopsia ***Lacrimation disorders: Dry eye, Lacrimal disorder and Lacrimation increased

Applies to: VIAGRA 50 mg orodispersible tablets

Summary of the safety profile

Tabulated list of adverse reactions

In the table below all medically important adverse reactions, which occurred in clinical studies at an incidence greater than placebo are listed by system organ class and frequency (very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000).. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ
Class
Very common
(≥ 1/10)
Common
(≥ 1/100 and
<1/10)
Uncommon
(≥ 1/1 000 and
<1/100)
Rare
(≥ 1/10 000 and <1/1 000)
Infections and infestations

Rhinitis

Immune system disorders

Hypersensitivity

Nervous system disorders
Headache
Dizziness
Somnolence,
Hypoaesthesia
Cerebrovascular accident,
Transient ischaemic attack,
Seizure*, Seizure recurrence,* Syncope
Eye disorders

System Organ
Class
Very common
(≥ 1/10)
Common
(≥ 1/100 and
<1/10)
Uncommon
(≥ 1/1 000 and
<1/100)
Rare
(≥ 1/10 000 and <1/1 000) disorder, Mydriasis, Halo vision, Eye oedema, Eye swelling, Eye disorder, Conjunctival hyperaemia, Eye irritation, Abnormal sensation in eye, Eyelid oedema, Scleral discoloration Ear and labyrinth disorders

Vertigo,
Tinnitus
Deafness
Cardiac disorders

Tachycardia,
Palpitations
Sudden cardiac death*,
Myocardial infarction,
Ventricular arrhythmia*,
Atrial fibrillation, Unstable angina
Vascular disorders

Flushing, Hot flush
Hypertension,
Hypotension

Respiratory, thoracic and mediastinal disorders

Nasal congestion
Epistaxis, Sinus congestion
Throat tightness, Nasal oedema, Nasal dryness
Gastrointestinal disorders

Nausea,
Dyspepsia
Gastro oesophagael reflux disease,
Vomiting,
Abdominal pain upper, Dry mouth
Hypoaesthesia oral
Skin and subcutaneous tissue disorders

Rash
Stevens-Johnson Syndrome
(SJS)*, Toxic Epidermal
Necrolysis (TEN)*
Musculoskeletal and connective tissue disorders

Myalgia, Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Penile haemorrhage,
Priapism*,
Haematospermia, Erection increased

System Organ
Class
Very common
(≥ 1/10)
Common
(≥ 1/100 and
<1/10)
Uncommon
(≥ 1/1 000 and
<1/100)
Rare
(≥ 1/10 000 and <1/1 000)
General disorders and administration site conditions

Chest pain,
Fatigue, Feeling hot
Irritability
Investigations

Heart rate increased

Applies to: VIAGRA 50 mg orodispersible films

Summary of the safety profile

Tabulated list of adverse reactions

System Organ
Class
Very common
(≥1/10)
Common
(≥1/100 and
<1/10)
Uncommon
(≥1/1 000 and
<1/100)
Rare
(≥1/10 000 and <1/1 000)
Infections and infestations

Rhinitis

Immune system disorders

Hypersensitivity

Nervous system disorders
Headache
Dizziness
Somnolence,
Hypoaesthesia
Cerebrovascular accident,
Transient ischaemic attack,
Seizure*, Seizure recurrence*, Syncope
Eye disorders

Visual colour distortions**,
Visual disturbance,
Vision blurred
Lacrimation disorders***,
Eye pain,
Photophobia,
Photopsia,
Ocular hyperaemia,
Visual brightness,
Conjunctivitis
Non-arteritic anterior ischaemic optic neuropathy
(NAION)*, Retinal vascular occlusion*, Retinal haemorrhage,
Arteriosclerotic retinopathy, Retinal disorder, Glaucoma, Visual field defect, Diplopia, Visual acuity reduced, Myopia, Asthenopia, Vitreous floaters, Iris disorder, Mydriasis, Halo vision, Eye oedema, Eye swelling, Eye disorder, Conjunctival hyperaemia,

System Organ
Class
Very common
(≥1/10)
Common
(≥1/100 and
<1/10)
Uncommon
(≥1/1 000 and
<1/100)
Rare
(≥1/10 000 and <1/1 000)
Eye irritation, Abnormal sensation in eye, Eyelid oedema, Scleral discoloration
Ear and labyrinth disorders

Vertigo,
Tinnitus
Deafness
Cardiac disorders

Tachycardia,
Palpitations
Sudden cardiac death*,
Myocardial infarction,
Ventricular arrhythmia*,
Atrial fibrillation, Unstable angina
Vascular disorders

Flushing, Hot flush
Hypertension,
Hypotension

Respiratory, thoracic and mediastinal disorders

Nasal congestion
Epistaxis, Sinus congestion
Throat tightness, Nasal oedema, Nasal dryness
Gastrointestinal disorders

Nausea,
Dyspepsia
Gastro oesophagael reflux disease,
Vomiting,
Abdominal pain upper, Dry mouth
Hypoaesthesia oral
Skin and subcutaneous tissue disorders

Rash
Stevens-Johnson Syndrome
(SJS)*, Toxic Epidermal
Necrolysis (TEN)*
Musculoskeletal and connective tissue disorders

Myalgia, Pain in extremity

Renal and urinary disorders

Haematuria

Reproductive system and breast disorders

Penile haemorrhage,
Priapism*,
Haematospermia, Erection increased
General disorders and administration site conditions

Chest pain,
Fatigue, Feeling hot
Irritability

System Organ
Class
Very common
(≥1/10)
Common
(≥1/100 and
<1/10)
Uncommon
(≥1/1 000 and
<1/100)
Rare
(≥1/10 000 and <1/1 000)
Investigations

Heart rate increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.4 Special warnings and precautions for use

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets

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 (see section 5.1).
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 (see section 4.3).

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).

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 (see section 4.8). 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 (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 (see section 4.3).

Concomitant use with ritonavir

Co-administration of sildenafil with ritonavir is not advised (see section 4.5).

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 (see section 4.5). 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 (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.

Excipients

The film coating of the tablet contains lactose. VIAGRA should not be administered to men with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Women

VIAGRA is not indicated for use by women.

Applies to: VIAGRA 50 mg orodispersible tablets

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

VIAGRA potentiates the hypotensive effect of nitrates (see section 4.3).

Priapism

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

Effects on vision

Concomitant use with ritonavir

Co-administration of sildenafil with ritonavir is not advised (see section 4.5).

Concomitant use with alpha-blockers

Effect on bleeding

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Women

VIAGRA is not indicated for use by women.

Applies to: VIAGRA 50 mg orodispersible films

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

VIAGRA potentiates the hypotensive effect of nitrates (see section 4.3).

Priapism

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

Effects on vision

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 (see section 4.3).

Concomitant use with ritonavir

Co-administration of sildenafil with ritonavir is not advised (see section 4.5).

Concomitant use with alpha-blockers

Effect on bleeding

Women

VIAGRA is not indicated for use by women.

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets

Effects of other medicinal products on sildenafil

In vivo studies
Population pharmacokinetic analysis of clinical study 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. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is not advised (see section 4.4) 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 (1 200 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 (see section 4.2). 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). In normal 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 principal circulating metabolite. 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.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.

Although specific interaction studies were not conducted for all medicinal products, population pharmacokinetic analysis showed no effect of concomitant treatment on sildenafil pharmacokinetics when grouped as CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, loop and potassium sparing diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, beta-adrenoreceptor antagonists or inducers of CYP450 metabolism (such as rifampicin, barbiturates). 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

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 (see section 4.3).

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 (see sections 4.2 and 4.4). 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 medicinal products: 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 (see section 5.1).

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 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).

Applies to: VIAGRA 50 mg orodispersible tablets

Effects of other medicinal products on sildenafil

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. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is not advised (see section 4.4) 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 (1 200 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 (see section 4.2). 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). In normal 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 principal circulating metabolite. 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.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability 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

There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

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.

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 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).

Applies to: VIAGRA 50 mg orodispersible films

Effects of other medicinal products on sildenafil

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. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is not advised (see section 4.4) and in any event the maximum dose of sildenafil should under no circumstances exceed 25 mg within 48 hours.

pharmacokinetics (see section 4.2). 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). In normal 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 principal circulating metabolite. 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.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability 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

There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

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 (see sections 4.2 and 4.4). 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 medicinal products: 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 adverse events 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 (see section 5.1).

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 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).

4.6 Fertility, pregnancy and lactation

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets · VIAGRA 50 mg orodispersible tablets · VIAGRA 50 mg orodispersible films

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 (see section 5.1).

4.7 Effects on ability to drive and use machines

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets · VIAGRA 50 mg orodispersible tablets · VIAGRA 50 mg orodispersible films

VIAGRA has a minor influence on the ability to drive and use machines.

As dizziness and altered vision were reported in clinical studies with sildenafil, patients should be aware of how they react to VIAGRA, before driving or operating machinery.

4.9 Overdose

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets · VIAGRA 50 mg orodispersible tablets · VIAGRA 50 mg orodispersible films

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.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets · VIAGRA 50 mg orodispersible tablets · VIAGRA 50 mg orodispersible films

Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction, ATC Code: G04B E03.

Mechanism of action

Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during 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 is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects.

Pharmacodynamic effects

Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erection process. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximum recommended doses, there is an 80-fold selectivity over PDE1, and over 700-fold over PDE2, 3, 4, 7, 8, 9, 10 and 11. 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.

Clinical efficacy and safety

Two clinical studies were specifically designed to assess the time window after dosing during which sildenafil could produce an erection in response to sexual stimulation. In a penile plethysmography (RigiScan) study of fasted patients, the median time to onset for those who obtained erections of 60% rigidity (sufficient for sexual intercourse) was 25 minutes (range 12-37 minutes) on sildenafil. In a separate RigiScan study, sildenafil was still able to produce an erection in response to sexual stimulation 4-5 hours post-dose.

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5.2 Pharmacokinetic properties

Applies to: VIAGRA 25 mg film-coated tablets / VIAGRA 50 mg film-coated tablets / VIAGRA 100 mg film-coated tablets

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 oral bioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUC and Cmax increase in proportion with dose within the recommended dose range (25-100 mg).

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of 60 minutes and a mean reduction in Cmax of 29%.

Distribution

The mean steady state volume of distribution (Vd) for sildenafil is 105 L, indicating distribution into the tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free

plasma concentration for sildenafil of 18 ng/mL (38 nM). Protein binding is independent of total drug concentrations.

In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing.

Biotransformation

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.
This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for 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 h.

Elimination

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: VIAGRA 50 mg orodispersible tablets

Absorption

When film-coated tablets are taken with food, the rate of absorption of sildenafil is reduced with a mean delay in tmax of 60 minutes and a mean reduction in Cmax of 29%.

In a clinical study in 36 healthy males 45 years or older, 50 mg orodispersible tablets administered without water were observed to be bioequivalent to the 50 mg film-coated tablets. In the same study, the AUC was unchanged but the mean Cmax was 14% lower when 50 mg orodispersible tablets were administered with water compared to 50 mg film-coated tablet.

When orodispersible tablets is taken with a high fat meal, the rate of absorption of sildenafil is reduced, median Tmax is delayed by about 3.4 hours and mean Cmax and AUC are reduced respectively by about 59% and 12%, compared to administration of orodispersible tablets under fasting conditions (see section 4.2).

Distribution

In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing.

Biotransformation

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: VIAGRA 50 mg orodispersible films

Absorption

Film-coated tablets
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 oral bioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUC and Cmax increase in proportion with dose within the recommended dose range (25-100 mg).

When film-coated tablets are taken with food, the rate of absorption of sildenafil is reduced with a mean delay in tmax of 60 minutes and a mean reduction in Cmax of 29%.

Orodispersible films
In a clinical study in 80 healthy males 20-43 years of age, sildenafil 50 mg orodispersible films administered without water were observed to be bioequivalent to the sildenafil 50 mg film-coated tablets.
In another study in 40 healthy males 23-54 years of age, sildenafil 50 mg orodispersible films administered with water were observed to be bioequivalent to the sildenafil 50 mg film-coated tablets.
The effect of food on sildenafil 50 mg orodispersible films has not been studied, however an effect of food similar to that seen on sildenafil 50 mg orodispersible tablets is expected (see “Orodispersible tablets” below and section 4.2).

Orodispersible tablets
When orodispersible tablets are taken with a high fat meal, the rate of absorption of sildenafil is reduced, median tmax is delayed by about 3.4 hours and mean Cmax and AUC are reduced respectively by about 59% and 12%, compared to administration of orodispersible tablets under fasting conditions (see section 4.2).

Distribution

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Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.