Revatio 0.8 mg/ml solution for injection

Each ml of solution contains 0.8 mg of sildenafil (as citrate). Each 20 ml vial contains 12.5 ml of solution (10 mg of sildenafil, as citrate).

Excipient(s) with known effects

For the full list of excipients, (see section 6.1).

Solution for injection.

Clear, colourless solution.

Revatio solution for injection is for the treatment of adult patients 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.

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.

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.

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. Dose adjustments of sildenafil may be required when co-administered with CYP3A4 inducers (see section 4.5). For the use of sildenafil with the most potent CYP3A4 inhibitors, (see section 4.3).

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.

Discontinuation of treatment

Limited data suggests 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.

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).

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.

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.

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).

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.

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.

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.

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).

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

Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported in connection with the intake of sildenafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should stop taking Revatio and consult a physician immediately (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.

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 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, bosentan, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration. There is a pharmacokinetic interaction between sildenafil and bosentan (see below information on the interaction with CYP3A4 inducers and effects of sildenafil on other medicinal products).

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

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. Caution is recommended in case of co-administration.

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 C_max 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 C_max and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. For dose recommendations (see sections 4.2).

When a single 100 mg dose of oral sildenafil was administered with erythromycin, a specific 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 sections 4.2). In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, C_max, T_max, 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). Caution is recommended in case of co-administration.

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.

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).

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

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).

Breastfeeding

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

It is not known whether sildenafil enters the breast milk. Revatio should not be administered to breast-feeding mothers.

Fertility

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

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.

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 a 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 drug. 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 treated with oral Revatio at daily doses ranging from 20 mg to 80 mg three times a day and 70 patients were treated with placebo. The duration of treatment was 12 weeks. 259 subjects who completed the pivotal study 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 studied (N = 149 patients treated for at least 1 year, 101 on 80 mg three times a day). The overall frequency of discontinuation in sildenafil treated patients at the recommended daily dose of 20 mg three times a day (2.9 %) was low and the same as placebo (2.9 %).

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) 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 bloodshot eyes/red eyes, blurred vision, 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.

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 limb pain.

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 three times a day 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, undesirable effects are presented in order of decreasing seriousness.

Reports from post-marketing experience are included in italics.

Description of selected adverse reactions

* Sudden decrease or loss of hearing has been reported in a small number of post-marketing and clinical trial cases with the use of all PDE5 inhibitors, including sildenafil.

In post marketing surveillance, adverse events/reactions that have been reported with an unknown frequency in patients taking sildenafil in the treatment of male erectile dysfunction (MED) include:

Eye disorders: Non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vascular occlusion, visual field defect.

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.

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 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 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.

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 of intravenous sildenafil in adult patients with pulmonary arterial hypertension (PAH)

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. This is based on Pharmacokinetic data only (see section 5.2. Pharmacokinetic Properties). The consequences of the subsequent lower exposure to the active N-desmethyl metabolite observed after repeated IV administration of Revatio have not been documented. No clinical studies have been performed to demonstrate that these formulations have comparable efficacy

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 PAH who were already receiving and stable on oral Revatio 20 mg TID.

A total of 10 PAH subjects enrolled and completed the study. Eight subjects were taking bosentan and one subject was taking treprostinil in addition to bosentan and Revatio. After dosing, sitting and standing blood pressure and heart rate were recorded at 30, 60, 120, 180 and 360 minute post dose. The mean changes from baseline in sitting blood pressure were greatest at 1 hour, -9.1 mmHg (SD ± 12.5) and -3.0 (SD ± 4.9) mmHg for systolic and diastolic pressure respectively. The mean postural changes in systolic and diastolic blood pressure over time were small (< 10 mmHg) and returned towards baseline beyond 2 hours.

Efficacy of oral sildenafil 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 (CTD), 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 (CTD) 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. A statistically significant increase in 6-minute walk distance was observed in all 3 sildenafil dose groups compared to those on placebo. Placebo corrected increases in walk distance 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 respectively. There was no significant difference in effect between sildenafil doses.

When analysed by WHO functional class, a statistically significant increase in 6-minute walk distance 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 walk distance 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 baseline walking distance, aetiology (primary and CTD-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) compared to those on placebo. The placebo-corrected treatment was -2.7 mmHg (p = 0.04) for sildenafil 20 mg three times a day. There was no evidence of a difference in effect between sildenafil 20 mg and the higher doses tested. The mean change from baseline in pulmonary vascular resistance (PVR) was -122 dyne.sec/cm⁵ for sildenafil 20 mg three times a day. The percent reduction at 12 weeks for sildenafil 20 mg in PVR (11.2 %) was proportionally greater than the reduction in systemic vascular resistance (SVR) (7.2 %). The effect of sildenafil on mortality is unknown.

Long-term survival data

Patients enrolled into the pivotal oral route study were eligible to enter a long term open label extension study. A total of 207 patients were treated with Revatio 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 of oral sildenafil 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 CTD (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) 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 CTD. 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 %).

Absorption

The mean absolute oral bioavailability for sildenafil is 41% (range 25-63 %). In study A1481262 C_max, CL and AUC (0-8) of 248 ng/ml, 30.3 L/h and 330 ng h/ml, were observed respectively. The C_max 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

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 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 oral 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.

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 intravenous exposure at 10 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.

Glucose

Water for injections

This medicinal product must not be mixed with other medicinal products or intravenous diluents except those mentioned in section 6.6.

3 years.

This medicinal product does not require any special storage conditions.

Each pack contains one 20 ml clear, type I glass vial with a chlorobutyl rubber stopper and an aluminium overseal.

This medicinal product does not require dilution or reconstitution before use.

One 20 ml vial contains 10 mg of sildenafil (as citrate). The recommended dose of 10 mg requires a volume of 12.5 ml, to be administered as an intravenous bolus injection.

Chemical and physical compatibility has been demonstrated with the following diluents:

5% glucose solution

sodium chloride 9mg/ml (0.9 %) solution

Lactated Ringer's solution

5 % glucose/0.45 % sodium chloride solution

5 % glucose/lactated Ringer's solution

5 % glucose/20 mEq potassium chloride solution

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

Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom.

EU/1/05/318/002

Date of first authorisation: 28 October 2005

Date of latest renewal: 28 October 2010

04/2012

Prescription-only medicinal product

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu