Bifort-M

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.

Bifort-M 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 Bifort-M to be effective, sexual stimulation is required.

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 Bifort-M 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 Bifort-M 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 (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.1).

Patients using other medicinal products

In general, any dose adjustment should be administered only after a careful benefit-risk assessment. Dose adjustments for sildenafil may be required when co-administered with CYP3A4 inducers.

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.

Bifort-M is contraindicated in patients with severe hepatic impairment (Child-Pugh class C),.

Paediatric population

The safety and efficacy of Bifort-M 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 Bifort-M 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

Bifort-M powder for oral suspension is for oral use only. The constituted 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.

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 Bifort-M is taken with food, the onset of activity may be delayed compared to the fasted state.

Special populations

Elderly

Dosage adjustments are not required in elderly patients (> 65 years old).

Renal impairment

The dosing recommendations described in “Use in adults” apply to patients with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min).

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min) a 25 mg dose should be considered. Based on efficacy and tolerability, the dose may be increased 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

Bifort-M 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 a starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors.

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.

Method of administration

For oral use.

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

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.

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

Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated:

Severe hepatic impairment,

Recent history of stroke or myocardial infarction,

Severe hypotension (blood pressure < 90/50 mmHg) at initiation.

Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway , sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.

The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension.

Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure).

Bifort-M is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: severe hepatic impairment, hypotension (blood pressure < 90/50 mmHg), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

The efficacy of Bifort-M 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. 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. 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.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.

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.

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 Bifort-M 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. In the event of any sudden visual defect, the treatment should be stopped immediately and alternative treatment should be considered.

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. 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.

Fructose intolerance

The powder contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Use of sildenafil with bosentan

The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated.

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.

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

Cardiovascular risk factors

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. Prior to prescribing sildenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.

Bifort-M potentiates the hypotensive effect of nitrates.

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

Priapism

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

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an erection that persists for longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

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

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

Effects on vision

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

Concomitant use with ritonavir

Co-administration of sildenafil with ritonavir is not advised.

Concomitant use with alpha-blockers

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

Effect on bleeding

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

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

Women

Bifort-M is not indicated for use by women.

Bifort-M 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 Bifort-M, before driving or using machines.

No studies on the effects on the ability to drive and use machines have been performed.

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

Summary of the safety profile

In the pivotal placebo-controlled study of Bifort-M 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 Bifort-M 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 Bifort-M 80 mg TID.

In a placebo-controlled study of Bifort-M as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with Bifort-M (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 Bifort-M 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 Bifort-M compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.

Tabulated list of adverse reactions

Adverse reactions which occurred in > 1 % of Bifort-M-treated patients and were more frequent (> 1 % difference) on Bifort-M in the pivotal study or in the Bifort-M 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 the table 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.

*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 Bifort-M 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 Bifort-M 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 Bifort-M 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Summary of the safety profile

The safety profile of Bifort-M 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 blurred vision.

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 trials 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, undesirable effects 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

*Reported during post-marketing surveillance only

**Visual colour distortions: Chloropsia, Chromatopsia, Cyanopsia, Erythropsia and Xanthopsia

***Lacrimation disorders: Dry eye, Lacrimal disorder and Lacrimation 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.

United Kingdom

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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.

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated in the urine.

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 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.

Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).

Clinical efficacy and safety

Efficacy in adult patients with pulmonary arterial hypertension (PAH)

A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary pulmonary hypertension, PAH associated with connective tissue disease, and PAH following surgical repair of congenital heart lesions. Patients were randomised to one of four treatment groups: placebo, sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients (63 %) included were diagnosed with primary pulmonary hypertension, 84 (30 %) were diagnosed with PAH associated with connective tissue disease and 18 (7 %) of the patients were diagnosed with PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional Class II (107/277, 39 %) or III (160/277, 58 %) with a mean baseline 6 minute walking distance of 378 meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4 %) or IV (9/277, 3 %) at baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening fraction < 0.2 were not studied.

Sildenafil (or placebo) was added to patients' background therapy which could have included a combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy were excluded from the study.

The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance (6MWD). A statistically significant increase in 6MWD was observed in all 3 sildenafil dose groups compared to those on placebo. Placebo corrected increases in 6MWD were 45 metres (p < 0.0001), 46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID, respectively. There was no significant difference in effect between sildenafil doses. For patients with a baseline 6MWD < 325 m improved efficacy was observed with higher doses (placebo-corrected improvements of 58 metres, 65 metres and 87 metres for 20 mg, 40 mg and 80 mg doses TID, respectively).

When analysed by WHO functional class, a statistically significant increase in 6MWD was observed in the 20 mg dose group. For class II and class III, placebo corrected increases of 49 metres (p = 0.0007) and 45 metres (p = 0.0031) were observed respectively.

The improvement in 6MWD was apparent after 4 weeks of treatment and this effect was maintained at weeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary and connective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAP and PVRI.

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) compared to those on placebo. Placebo-corrected treatment effects with mPAP were -2.7 mmHg (p = 0.04), -3.0 mm Hg (p = 0.01) and -5.1 mm Hg (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID respectively. Placebo-corrected treatment effects with PVR were -178 dyne.sec/cm⁵ (p=0.0051), -195 dyne.sec/cm⁵ (p=0.0017) and -320 dyne.sec/cm⁵ (p<0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID, respectively. The percent reduction at 12 weeks for sildenafil 20 mg, 40 mg and 80 mg TID in PVR (11.2 %, 12.9 %, 23.3 %) was proportionally greater than the reduction in systemic vascular resistance (SVR) (7.2 %, 5.9 %, 14.4 %). The effect of sildenafil on mortality is unknown.

A greater percentage of patients on each of the sildenafil doses (i.e. 28 %, 36 % and 42 % of subjects who received sildenafil 20 mg, 40 mg and 80 mg TID doses, respectively) showed an improvement by at least one WHO functional class at week 12 compared to placebo (7 %). The respective odds ratios were 2.92 (p=0.0087), 4.32 (p=0.0004) and 5.75 (p<0.0001).

Long-term survival data in naive population

Patients enrolled into the pivotal study were eligible to enter a long term open label extension study. At 3 years 87 % of the patients were receiving a dose of 80 mg TID. A total of 207 patients were treated with Bifort-M in the pivotal study, and their long term survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 96 %, 91 % and 82 %, respectively. Survival in patients of WHO functional class II at baseline at 1, 2 and 3 years was 99 %, 91 %, and 84 % respectively, and for patients of WHO functional class III at baseline was 94 %, 90 %, and 81 %, respectively.

Efficacy in adult patients with PAH (when used in combination with epoprostenol)

A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who were stabilised on intravenous epoprostenol. The PAH patients included those with Primary Pulmonary Arterial Hypertension (212/267, 79 %) and PAH associated with connective tissue disease (55/267, 21 %). Most patients were WHO Functional Class II (68/267, 26 %) or III (175/267, 66 %); fewer patients were Class I (3/267, 1 %) or IV (16/267, 6 %) at baseline; for a few patients (5/267, 2 %), the WHO Functional Class was unknown. Patients were randomised to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) when used in combination with intravenous epoprostenol.

The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance. There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of sildenafil (95 % CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance > 325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with PAH associated with connective tissue disease. The difference in results between these randomisation subgroups may have arisen by chance in view of their limited sample size.

Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening was a secondary endpoint as defined as the time from randomisation to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Treatment with sildenafil significantly delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects experienced clinical worsening events in the placebo group (17.6 %) compared with 8 subjects in the sildenafil group (6.0 %).

Long-term Survival Data in the background epoprostenol study

Patients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term open label extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg TID. A total of 134 patients were treated with Bifort-M in the initial study, and their long term survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 92 %, 81 % and 74 %, respectively.

Efficacy and safety in adult patients with PAH (when used in combination with bosentan)

A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjects with PAH (WHO FC II and III) who were on bosentan therapy for a minimum of three months. The PAH patients included those with Primary PAH, and PAH associated with connective tissue disease. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil (20 mg three times a day) and placebo (13.62 m (95% CI: -3.89 to 31.12) and 14.08 m (95% CI: -1.78 to 29.95), respectively).

Differences in 6MWD were observed between patients with primary PAH and PAH associated with connective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baseline were 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52) for the sildenafil and placebo groups, respectively. However, for subjects with PAH associated with connective tissue disease (36 subjects) mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and 17.50 m (95% CI: -9.41 to 44.41) for the sildenafil and placebo groups, respectively.

Overall, the adverse events were generally similar between the two treatment groups (sildenafil plus bosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used as monotherapy.

Paediatric population

A total of 234 subjects aged 1 to 17 years were treated in a randomized, double-blind, multi-centre, placebo controlled parallel group, dose ranging study. Subjects (38 % male and 62 % female) had a body weight > 8 kg, and had primary pulmonary hypertension (PPH) [33 %], or PAH secondary to congenital heart disease [systemic-to-pulmonary shunt 37 %, surgical repair 30 %]. In this trial, 63 of 234 (27 %) patients were < 7 years old (sildenafil low dose = 2; medium dose = 17; high dose = 28; placebo = 16) and 171 of 234 (73 %) patients were 7 years or older (sildenafil low dose = 40; medium dose = 38; and high dose = 49; placebo = 44). Most subjects were WHO Functional Class I (75/234, 32 %) or II (120/234, 51 %) at baseline; fewer patients were Class III (35/234, 15 %) or IV (1/234, 0.4 %); for a few patients (3/234, 1.3 %), the WHO Functional Class was unknown.

Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted in the study, and neither was arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors.

The primary objective of the study was to assess the efficacy of 16 weeks of chronic treatment with oral sildenafil in paediatric subjects to improve exercise capacity as measured by the Cardiopulmonary Exercise Test (CPET) in subjects who were developmentally able to perform the test, n = 115). Secondary endpoints included haemodynamic monitoring, symptom assessment, WHO functional class, change in background treatment, and quality of life measurements.

Subjects were allocated to one of three sildenafil treatment groups, low (10 mg), medium (10-40 mg) or high dose (20-80 mg) regimens of Bifort-M given three times a day, or placebo. Actual doses administered within a group were dependent on body weight. The proportion of subjects receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (47.7 %) and the placebo treatment group (41.7 %).

The primary endpoint was the placebo-corrected percentage change in peak VO₂ from baseline to week 16 assessed by CPET in the combined dose groups (Table 2). A total of 106 out of 234 (45 %) subjects were evaluable for CPET, which comprised those children > 7 years old and developmentally able to perform the test. Children < 7 years (sildenafil combined dose = 47; placebo = 16) were evaluable only for the secondary endpoints. Mean baseline peak volume of oxygen consumed (VO₂) values were comparable across the sildenafil treatment groups (17.37 to 18.03 ml/kg/min), and slightly higher for the placebo treatment group (20.02 ml/kg/min). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p = 0.056) (see Table 2). The estimated difference between the medium sildenafil dose and placebo was 11.33 % (95 % CI: 1.72 to 20.94) (see Table 2).

Table 2: Placebo corrected % change from baseline in peak VO₂ by active treatment group

n=29 for placebo group

Estimates based on ANCOVA with adjustments for the covariates baseline peak VO₂, etiology and weight group

Dose related improvements were observed with pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP). The sildenafil medium and high dose groups both showed PVRI reductions compared to placebo, of 18 % (95 %CI: 2 % to 32 %) and 27 % (95 %CI: 14 % to 39 %), respectively; whilst the low dose group showed no significant difference from placebo (difference of 2 %). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of -3.5 mmHg (95 %CI: -8.9, 1.9) and -7.3 mmHg (95 %CI: -12.4, -2.1), respectively; whilst the low dose group showed little difference from placebo (difference of 1.6 mmHg). Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10 %, 4 % and 15 % for the low, medium and high dose groups respectively.

Significant improvements in functional class were demonstrated only in subjects on sildenafil high dose compared to placebo. Odds ratios for the sildenafil low, medium and high dose groups compared to placebo were 0.6 (95 % CI: 0.18, 2.01), 2.25 (95 % CI: 0.75, 6.69) and 4.52 (95 % CI: 1.56, 13.10), respectively.

Long term extension data

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered the long-term extension study. Subjects who had been in the placebo group in the short-term study were randomly reassigned to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium or high dose groups (1:1), while subjects weighing > 20 kg entered the low, medium or high dose groups (1:1:1). Of the total 229 subjects who received sildenafil, there were 55, 74, and 100 subjects in the low, medium and high dose groups, respectively. Across the short-term and long-term studies, the overall duration of treatment from start of double-blind for individual subjects ranged from 3 to 3129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1696 days (excluding the 5 subjects who received placebo in double-blind and were not treated in the long-term extension study).

Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94 %, 93 % and 85 % in the low, medium and high dose groups, respectively; for patients ≤ 20 kg in weight at baseline, the survival estimates were 94 % and 93 % for subjects in the medium and high dose groups respectively.

During the conduct of the study, there were a total of 42 deaths reported, whether on treatment or reported as part of the survival follow-up. 37 deaths occurred prior to a decision taken by the Data Monitoring Committee to down titrate subjects to a lower dosage, based on an observed mortality imbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. An additional 5 deaths were reported subsequently. The causes of deaths were related to PAH. Higher than recommended doses should not be used in paediatric patients with PAH.

Peak VO₂ was assessed 1 year after the start of the placebo-controlled study. Of those sildenafil treated subjects developmentally able to perform the CPET 59/114 subjects (52 %) had not shown any deterioration in Peak VO₂ from start of sildenafil. Similarly 191 of 229 subjects (83 %) who had received sildenafil had either maintained or improved their WHO Functional Class at 1 year assessment.

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 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.

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.

Sildenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure following 100 mg oral dosing of sildenafil was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mmHg. These decreases in blood pressure are consistent with the vasodilatory effects of sildenafil, probably due to increased cGMP levels in vascular smooth muscle. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

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.

A double-blind, placebo-controlled exercise stress trial evaluated 144 patients with erectile dysfunction and chronic stable angina who regularly received anti-anginal medicinal products (except nitrates). The results demonstrated no clinically relevant differences between sildenafil and placebo in time to limiting angina.

Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg) demonstrated no significant changes in the visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.

Further information on clinical trials

In clinical trials sildenafil was administered to more than 8000 patients aged 19-87. The following patient groups were represented: elderly (19.9%), patients with hypertension (30.9%), diabetes mellitus (20.3%), ischaemic heart disease (5.8%), hyperlipidaemia (19.8%), spinal cord injury (0.6%), depression (5.2%), transurethral resection of the prostate (3.7%), radical prostatectomy (3.3%). The following groups were not well represented or excluded from clinical trials: patients with pelvic surgery, patients post-radiotherapy, patients with severe renal or hepatic impairment and patients with certain cardiovascular conditions.

In fixed dose studies, the proportions of patients reporting that treatment improved their erections were 62% (25 mg), 74% (50 mg) and 82% (100 mg) compared to 25% on placebo. In controlled clinical trials, the discontinuation rate due to sildenafil was low and similar to placebo.

Across all trials, the proportion of patients reporting improvement on sildenafil were as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly (67%), diabetes mellitus (59%), ischaemic heart disease (69%), hypertension (68%), TURP (61%), radical prostatectomy (43%), spinal cord injury (83%), depression (75%). The safety and efficacy of sildenafil was maintained in long term studies.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Bifort-M in all subsets of the paediatric population for the treatment of erectile dysfunction.

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 C_max 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 T_max of 60 minutes and a mean reduction in C_max 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.

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 dosing (translating into a 36 % contribution to sildenafil's pharmacological effects). The subsequent effect on efficacy is unknown.

Elimination

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

Pharmacokinetics in special patient groups

Elderly

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

Renal insufficiency

In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml/min), the pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. In volunteers with severe renal impairment (creatinine clearance < 30 ml/min), sildenafil clearance was reduced, resulting in mean increases in AUC and C_max of 100 % and 88 % respectively compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C_max values were significantly increased by 200 % and 79 % respectively in subjects with severe renal impairment compared to subjects with normal renal function.

Hepatic insufficiency

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) sildenafil clearance was reduced, resulting in increases in AUC (85 %) and C_max (47 %) compared to age-matched volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and C_max values were significantly increased by 154 % and 87 %, respectively in cirrhotic subjects compared to subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been studied.

Population pharmacokinetics

In patients with pulmonary arterial hypertension, the average steady state concentrations were 20-50 % higher over the investigated dose range of 20-80 mg three times a day compared to healthy volunteers. There was a doubling of the C_min compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterial hypertension compared to healthy volunteers.

Paediatric population

From the analysis of the pharmacokinetic profile of sildenafil in patients involved in the paediatric clinical trials, body weight was shown to be a good predictor of drug exposure in children. Sildenafil plasma concentration half-life values were estimated to range from 4.2 to 4.4 hours for a range of 10 to 70 kg of body weight and did not show any differences that would appear as clinically relevant. C_max after a single 20 mg sildenafil dose administered PO was estimated at 49, 104 and 165 ng/ml for 70, 20 and 10 kg patients, respectively. C_max after a single 10 mg sildenafil dose administered PO was estimated at 24, 53 and 85 ng/ml for 70, 20 and 10 kg patients, respectively. T_max was estimated at approximately 1 hour and was almost independent from body weight.

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 C_max increase in proportion with dose over the recommended dose range (25-100 mg).

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

Distribution

The mean steady state volume of distribution (V_d) 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

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

Pharmacokinetics in special patient groups

Elderly

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

Renal insufficiency

In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min), the pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. The mean AUC and C_max of the N-desmethyl metabolite increased up to 126% and up to 73% respectively, compared to age-matched volunteers with no renal impairment. However, due to high inter-subject variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and C_max of 100% and 88% respectively compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C_max values were significantly increased by 200% and 79% respectively.

Hepatic insufficiency

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced, resulting in increases in AUC (84%) and C_max (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been studied.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, toxicity to reproduction and development.

In pups of rats which were pre- and postnatally treated with 60 mg/kg sildenafil, a decreased litter size, a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were approximately fifty times the expected human exposure at 20 mg three times a day. Effects in non-clinical studies were observed at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

There were no adverse reactions, with possible relevance to clinical use, seen in animals at clinically relevant exposure levels which were not also observed in clinical studies.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

Not applicable.

Not applicable.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

It is recommended that a pharmacist constitutes Bifort-M oral suspension prior to its dispensing to the patient.

Reconstitution instructions

Note: A total volume of 90 ml (3 x 30 ml) of water irrespective of the dose to be taken should be used to reconstitute the contents of the bottle

1. Tap the bottle to release the powder.

2. Remove the cap.

3. Measure 30 ml of water by filling the measuring cup (included in the carton) to the marked line then pour the water into the bottle. Using the cup measure another 30 ml of water and add this to the bottle (figure 1).

4. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds (figure 2).

5. Remove the cap.

6. Using the cup measure another 30 ml of water and add this to the bottle. You should always add a total of 90 ml (3 x 30 ml) of water irrespective of the dose you are taking (figure 3).

7. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds (figure 4).

8. Remove the cap.

9. Press the bottle adaptor into the neck of the bottle (as shown on figure 5 below). The adaptor is provided so that you can fill the oral dosing syringe with medicine from the bottle. Replace the cap on the bottle.

10. When constituted the powder provides a white grape flavoured oral suspension. Write the date of expiry of the constituted oral suspension on the bottle label (the date of expiry of the constituted oral suspension is 30 days from the date of constitution). Any unused oral suspension should be discarded or returned to your pharmacist after this date.

Instructions for use

1. Shake the closed bottle of constituted oral suspension vigorously for a minimum of 10 seconds before use. Remove the cap (figure 6).

2. While the bottle is upright, on a flat surface, insert the tip of the oral dosing syringe into the adaptor (figure 7).

3. Turn the bottle upside down while holding the oral dosing syringe in place. Slowly pull back the plunger of the oral dosing syringe to the graduation mark that marks the dose for you (withdrawing 1 ml provides a 10 mg dose, withdrawing 2 ml provides a 20 mg dose). To measure the dose accurately, the top edge of the plunger should be lined up with the appropriate graduated mark on the oral dosing syringe (figure 8).

4. If large bubbles can be seen, slowly push the plunger back into the syringe. This will force the medicine back into the bottle. Repeat step 3 again.

5. Turn the bottle back upright with the oral dosing syringe still in place. Remove the oral dosing syringe from the bottle.

6. Put the tip of the oral dosing syringe into the mouth. Point the tip of the oral dosing syringe towards the inside of the cheek. SLOWLY push down the plunger of the oral dosing syringe. Do not squirt the medicine out quickly. If the medicine is to be given to a child, make sure the child is sitting, or is held, upright before giving the medicine (figure 9).

7. Replace the cap on the bottle, leaving the bottle adaptor in place. Wash the oral dosing syringe as instructed below.

Cleaning and storing the syringe:

1. The syringe should be washed after each dose. Pull the plunger out of the syringe and wash both parts in water.

2. Dry the two parts. Push the plunger back in to the syringe. Keep it in a clean safe place with the medicine.

Once reconstituted, the oral suspension should only be administered using the oral dosing syringe supplied with each pack. Refer to the patient leaflet for more detailed instructions for use.

No special requirements.