REVATIO 20mg tablets medication leaflet

Revatio 20 mg film-coated tablets

Each film-coated tablet contains 20 mg of sildenafil (as citrate).

Each tablet also contains 0.7 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet.

White, round, biconvex film-coated tablets marked “VLE” on one side and “RVT 20” on the other.

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

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 shownin primary pulmonary hypertension and pulmonary hypertension associated with congenital heartdisease (see section 5.1).

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

The recommended dose is 20 mg three times a day (TID). Physicians should advise patients whoforget to take Revatio to take a dose as soon as possible and then continue with the normal dose.

Patients should not take a double dose to compensate for the missed dose.

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

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

Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walkdistance could be less in elderly patients.

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

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 carefulbenefit-risk assessment only if therapy is not well-tolerated.

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

Outside its authorised indications, sildenafil should not be used in neonates with persistent pulmonaryhypertension of the newborn as risks outweigh the benefits (see section 5.1). The safety and efficacyof Revatio in other conditions in children below 1 year of age has not been established. No data areavailable.

Limited data suggest that the abrupt discontinuation of Revatio is not associated with reboundworsening of pulmonary arterial hypertension. However to avoid the possible occurrence of suddenclinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensifiedmonitoring is recommended during the discontinuation period.

Revatio is for oral use only. Tablets should be taken approximately 6 to 8 hours apart with or withoutfood.

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 thehypotensive effects of nitrates (see section 5.1).

The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators,such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section4.5).

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

Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic opticneuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5inhibitor exposure (see section 4.4).

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

Severe hepatic impairment,

Recent history of stroke or myocardial infarction,

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

The efficacy of Revatio has not been established in patients with severe pulmonary arterialhypertension (functional class IV). If the clinical situation deteriorates, therapies that arerecommended at the severe stage of the disease (eg, epoprostenol) should be considered (see section4.2). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHOfunctional class I pulmonary arterial hypertension.

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

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

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

When prescribing sildenafil, physicians should carefully consider whether patients with certainunderlying conditions could be adversely affected by sildenafil’s mild to moderate vasodilatoryeffects, for example patients with hypotension, patients with fluid depletion, severe left ventricularoutflow obstruction or autonomic dysfunction (see section 4.4).

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascularevents, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia,cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have beenreported 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 sexualintercourse 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 otherfactors.

Sildenafil should be used with caution in patients with anatomical deformation of the penis (such asangulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which maypredispose 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. Inthe event of an erection that persists longer than 4 hours, the patient should seek immediate medicalassistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potencycould result (see section 4.8).

Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cellanaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reportedmore commonly by patients receiving Revatio than those receiving placebo leading to the prematuretermination of this study.

Cases of visual defects have been reported spontaneously in connection with the intake of sildenafiland 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 intakeof sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual defect, thetreatment should be stopped immediately and alternative treatment should be considered (see section4.3).

Caution is advised when sildenafil is administered to patients taking an alpha-blocker as theco-administration may lead to symptomatic hypotension in susceptible individuals (see section 4.5). Inorder to minimise the potential for developing postural hypotension, patients should behaemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physiciansshould advise patients what to do in the event of postural hypotensive symptoms.

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

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

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

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

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

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

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

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (majorroute) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafilclearance and inducers of these isoenzymes may increase sildenafil clearance. For doserecommendations, see sections 4.2 and 4.3.

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

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

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

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated areduction 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 theonly factors with a statistically significant impact on sildenafil pharmacokinetics in patients withpulmonary 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 patientsnot receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mgthree times a day compared to the exposure at a dose of 20 mg three times a day. This concentrationrange covers the increase in sildenafil exposure observed in specifically designed drug interactionstudies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg,ketoconazole, itraconazole, ritonavir).

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

CYP3A4 inducer bosentan.

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

Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4inducers, 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, atsteady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300 % (4-fold)increase in sildenafil Cmax and a 1,000 % (11-fold) increase in sildenafil plasma AUC. At 24 hours, theplasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/mlwhen sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broadrange of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil withritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state(1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140 % increase insildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavirpharmacokinetics. For dose recommendations, see section 4.2.

When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in sildenafilsystemic exposure (AUC). For dose recommendations, see section 4.2. In healthy male volunteers,there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax,elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite.

No dose adjustment is required. Cimetidine (800 mg), a cytochrome P450 inhibitor and a non-specific

CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil concentrations when co-administeredwith 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 expectedto 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 CYP3A4inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. Thereforedose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).

The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested thatco-administration of beta-blockers in combination with CYP3A4 substrates might result in anadditional 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 modestincreases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use ofsildenafil and grapefruit juice is not recommended.

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

Co-administration of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg) did notaffect the pharmacokinetics of sildenafil.

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

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 astheophylline or dipyridamole.

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

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

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

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

Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers withmean maximum blood alcohol levels of 80 mg/dl.

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

In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine inhypertensive 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. Theseadditional blood pressure reductions were of a similar magnitude to those seen when sildenafil wasadministered alone to healthy volunteers.

In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) andsildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benignprostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, meanadditional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and8/4 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 wereadministered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reportsof patients who experienced symptomatic postural hypotension. These reports included dizziness andlightheadedness, but not syncope. Concomitant administration of sildenafil to patients takingalpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section4.4).

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

Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil wasshown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxidedonors or nitrates in any form is therefore contraindicated (see section 4.3).

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment thehypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of thecombination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, includingsildenafil, is contraindicated (see section 4.3).

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

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

Interaction studies have only been performed in adults.

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

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

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

There are no adequate and well controlled studies in lactating women. Data from one lactating womanindicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk atvery low levels. No clinical data are available regarding adverse events in breast-fed infants, butamounts ingested would not be expected to cause any adverse effects. Prescribers should carefullyassess the mother’s clinical need for sildenafil and any potential adverse effects on the breast-fedchild.

Non-clinical data revealed no special hazard for humans based on conventional studies of fertility (seesection 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 awareof how they might be affected by Revatio, before driving or using machines.

In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg TID doses of Revatio and70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overallfrequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TIDwas 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the 277 subjects treatedin the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day(4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 %of 183 patients on study treatment were receiving Revatio 80 mg TID.

In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonaryarterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting from20 mg, to 40 mg and then 80 mg, three times a day, as tolerated) and epoprostenol, and 131 patientswere treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overallfrequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adversereactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocularhyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The knownadverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequencyin sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of thesubjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg

TID were administered and after 3 years 68 % of 133 patients on study treatment were receiving

Revatio 80 mg TID.

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

In a study to assess the effects of different dose levels of sildenafil the safety data for sildenafil 20 mg

TID (recommended dose) and for sildenafil 80 mg TID (4 times the recommended dose), wereconsistent with the established safety profile of sildenafil in previous adult PAH studies.

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 theplacebo-controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg TID arelisted in Table 1 below by class and frequency grouping (very common (≥ 1/10), common (≥ 1/100 to< 1/10), uncommon (≥ 1/1000 to < 1/100) and not known (cannot be estimated from the availabledata). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Reports from post-marketing experience are included in italics.

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

MedDRA system organ class (V.14.0) Adverse reaction

Common cellulitis, influenza, bronchitis,sinusitis, rhinitis, gastroenteritis

Common anaemia

Common fluid retention

Common insomnia, anxiety

Very common headache

Common migraine, tremor, paraesthesia, burningsensation, hypoaesthesia

Common retinal haemorrhage, visualimpairment, vision blurred,photophobia, chromatopsia, cyanopsia,eye irritation, ocular hyperaemia

Uncommon visual acuity reduced, diplopia,abnormal sensation in eye

Not known Non-arteritic anterior ischaemic opticneuropathy (NAION)*, Retinalvascular occlusion*, Visual fielddefect*

Ear and labyrinth disorders

Common vertigo

Not known sudden hearing loss

Very common flushing

Not Known hypotension

Common epistaxis, cough, nasal congestion

Very common diarrhoea, dyspepsia

Common gastritis, gastrooesophageal refluxdisease, haemorrhoids, abdominaldistension, dry mouth

Common alopecia, erythema, night sweats

Not known rash

Very common pain in extremity

Common myalgia, back pain

Uncommon haematuria

Uncommon penile haemorrhage, haematospermia,gynaecomastia

Not known priapism, erection increased

General disorders and administration siteconditions

Common pyrexia

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

In the placebo-controlled study of Revatio in patients 1 to 17 years of age with pulmonary arterialhypertension, 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 inpatients ≥ 20-45 kg; 40 mg in patients > 45 kg) or high dose (20 mg in patients ≥ 8-20 kg; 40 mg inpatients ≥ 20-45 kg; 80 mg in patients > 45 kg) regimens of Revatio and 60 were treated with placebo.

The adverse reactions profile seen in this paediatric study was generally consistent with that in adults(see table above). The most common adverse reactions that occurred (with a frequency ≥ 1 %) in

Revatio patients (combined doses) and with a frequency > 1 % over placebo patients were pyrexia,upper respiratory tract infection (each 11.5%), vomiting (10.9%), erection increased (includingspontaneous 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 enteredthe long-term extension study. Subjects on active sildenafil therapy continued on the same treatmentregimen, while those in the placebo group in the short-term study were randomly reassigned tosildenafil treatment.

The most common adverse reactions reported across the duration of the short-term and long-termstudies 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 notcontinue 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 94subjects 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 commonserious 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 tractinfection (3.1%), right ventricular failure, gastroenteritis (each 2.6%), syncope, bronchitis,bronchopneumonia, pulmonary arterial hypertension (each 2.2%), chest pain, dental caries (each1.7%), 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specificphosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart fromthe presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in thepulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smoothmuscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead tovasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemiccirculation.

Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involvedin the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-foldselectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the controlof cardiac contractility.

Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority ofcases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patientswith systemic hypertension the mean change from baseline in systolic and diastolic blood pressure wasa decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a dayto patients with pulmonary arterial hypertension lesser effects in blood pressure reduction wereobserved (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of20 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 relevanteffects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterialhypertension 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 withsevere coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the meanresting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared tobaseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect oncardiac 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 subjectsusing the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evidentafter 2 hours post-dose. The postulated mechanism for this change in colour discrimination is relatedto inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil hasno effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patientswith 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, colourdiscrimination simulated traffic light, Humphrey perimeter and photostress).

A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primarypulmonary hypertension, PAH associated with connective tissue disease, and PAH following surgicalrepair 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 patientsrandomised, 277 patients received at least 1 dose of study drug. The study population consisted of68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline6-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 diagnosedwith 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 of378 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 acombination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use ofprostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-ontherapy, and neither was arginine supplementation. Patients who previously failed bosentan therapywere 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 groupscompared 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 TIDrespectively. There was no significant difference in effect between sildenafil doses. For patients with abaseline 6MWD < 325 m improved efficacy was observed with higher doses (placebo-correctedimprovements 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 observedin 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 atweeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary andconnective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAPand PVRI.

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterialpressure (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 subjectswho received sildenafil 20 mg, 40 mg and 80 mg TID doses, respectively) showed an improvement byat least one WHO functional class at week 12 compared to placebo (7 %). The respective odds ratioswere 2.92 (p=0.0087), pct. 4.32 (p=0.0004) and 5.75 (p<0.0001).

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 weretreated with Revatio in the pivotal study, and their long term survival status was assessed for aminimum 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 and3 years was 99 %, 91 %, and 84 % respectively, and for patients of WHO functional class III atbaseline was 94 %, 90 %, and 81 %, respectively.

A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH whowere 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 (ina fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) whenused 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 walkdistance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour ofsildenafil (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 baselinewalking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patientswith primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with PAHassociated with connective tissue disease. The difference in results between these randomisationsubgroups 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 effectof -3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time toclinical worsening was a secondary endpoint as defined as the time from randomisation to the firstoccurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, orclinical deterioration requiring a change in epoprostenol therapy). Treatment with sildenafilsignificantly 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 with8 subjects in the sildenafil group (6.0 %).

Patients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term openlabel extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg TID. A total of134 patients were treated with Revatio in the initial study, and their long term survival status wasassessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 yearsurvival were 92 %, 81 % and 74 %, respectively.

A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjectswith 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 withbosentan (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 frombaseline 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 withconnective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baselinewere 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52) for the sildenafil andplacebo groups, respectively. However, for subjects with PAH associated with connective tissuedisease (36 subjects) mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and17.50 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 plusbosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used asmonotherapy (see sections 4.4 and 4.5).

Effects on mortality in adults with PAH

A study to investigate the effects of different dose levels of sildenafil on mortality in adults with PAHwas conducted following the observation of a higher risk of mortality in paediatric patients taking ahigh dose of sildenafil TID, based on body weight, compared to those taking a lower dose in thelong-term extension of the paediatric clinical trial (see below Paediatric population - Pulmonaryarterial hypertension - Long term extension data).

The study was a randomized, double-blind, parallel-group study in 385 adults with PAH. Patients wererandomly assigned 1:1:1 to one of three dosage groups (5 mg TID (4 times lower than therecommended dose), 20 mg TID (recommended dose) and 80 mg TID (4 times the recommendeddose)). In total, the majority of subjects were PAH treatment naïve (83.4%). For most subjects theetiology of PAH was idiopathic (71.7%). The most common WHO Functional Class was Class III(57.7% of subjects). All three treatment groups were well balanced with respect to baselinedemographics of strata history of PAH-treatment and etiology of PAH, as well as the WHO Functional

Class categories.

The mortality rates were 26.4% (n=34) for the 5 mg TID dose, 19.5% (n=25) for the 20 mg TID doseand 14.8% (n=19) with the 80 mg TID dose.

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 abody weight ≥ 8 kg, and had primary pulmonary hypertension (PPH) [33 %], or PAH secondary tocongenital heart disease [systemic-to-pulmonary shunt 37 %, surgical repair 30 %]. In this trial, 63 of234 (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; mediumdose = 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 andendothelin receptor antagonists was not permitted in the study, and neither was argininesupplementation, 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 withoral 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 functionalclass, 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 Revatio given three times a day, or placebo. Actual dosesadministered within a group were dependent on body weight (see Section 4.8). The proportion ofsubjects receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channelblockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (47.7 %) andthe placebo treatment group (41.7 %).

The primary endpoint was the placebo-corrected percentage change in peak VO2 from baseline toweek 16 assessed by CPET testing 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 anddevelopmentally 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 oxygenconsumed (VO2) values were comparable across the sildenafil treatment groups (17.37 to18.03 ml/kg/min), and slightly higher for the placebo treatment group (20.02 ml/kg/min). The resultsof the main analysis (combined dose groups vs. 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

Treatment group Estimated difference 95% confidence interval

Low dose 3.81 -6.11, 13.73(n=24)

Medium dose 11.33 1.72, 20.94(n=26)

High dose 7.98 -1.64, 17.60(n=27)

Combined dose groups 7.71 -0.19, 15.60(n=77) (p = 0.056)n=29 for placebo group

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

Dose related improvements were observed with pulmonary vascular resistance index (PVRI) and meanpulmonary arterial pressure (mPAP). The sildenafil medium and high dose groups both showed PVRIreductions 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 of2 %). The sildenafil medium and high dose groups displayed mPAP changes from baseline comparedto 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 highdose compared to placebo. Odds ratios for the sildenafil low, medium and high dose groups comparedto 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.

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects enteredthe long-term extension study. Subjects who had been in the placebo group in the short-term studywere randomly reassigned to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium orhigh 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 thelow, medium and high dose groups, respectively. Across the short-term and long-term studies, theoverall duration of treatment from start of double-blind for individual subjects ranged from3 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-termextension 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 weightat baseline, the survival estimates were 94 % and 93 % for subjects in the medium and high dosegroups respectively (see sections 4.4 and 4.8).

During the conduct of the study, there were a total of 42 deaths reported, whether on treatment orreported 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 mortalityimbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was5/55 (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 (seesections 4.2 and 4.4).

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

A randomized, double-blind, two-arm, parallel-group, placebo-controlled study was conducted in59 neonates with persistent pulmonary hypertension of the newborn (PPHN), or hypoxic respiratoryfailure (HRF) and at risk for PPHN with oxygenation index (OI) >15 and <60. The primary objectivewas to evaluate the efficacy and safety of IV sildenafil when added to inhaled nitric oxide (iNO)compared with iNO alone.

The co-primary endpoints were treatment failure rate, defined as need for additional treatmenttargeting PPHN, need for extracorporeal membrane oxygenation (ECMO), or death during the study;and time on iNO treatment after initiation of IV study drug for patients without treatment failure. Thedifference in treatment failure rates was not statistically significant between the two treatment groups(27.6% and 20.0% in the iNO + IV sildenafil group and iNO + placebo group, respectively). Forpatients without treatment failure, the mean time on iNO treatment after initiation of IV study drugwas the same, approximately 4.1 days, for the two treatment groups.

Treatment-emergent adverse events and serious adverse events were reported in 22 (75.9%) and7 (24.1%) subjects in the iNO + IV sildenafil treatment group, respectively, and in 19 (63.3%) and2 (6.7%) subjects in the iNO + placebo group, respectively. The most commonly reportedtreatment-emergent adverse events were hypotension (8 [27.6%] subjects), hypokalaemia (7 [24.1%]subjects), anaemia and drug withdrawal syndrome (4 [13.8%] subjects each) and bradycardia(3 [10.3%] subjects) in the iNO + IV sildenafil treatment group and pneumothorax (4 [13.3%]subjects), anaemia, oedema, hyperbilirubinaemia, C-reactive protein increased, and hypotension(3 [10.0%] subjects each) in the iNO + placebo treatment group (see section 4.2).

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oralbioavailability is 41 % (range 25-63 %). After oral three times a day dosing of sildenafil, AUC and

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

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in Tmax of60 minutes and a mean reduction in Cmax of 29 % however, the extent of absorption was notsignificantly affected (AUC decreased by 11 %).

The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution intothe tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentrationof 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 isindependent of total drug concentrations.

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepaticmicrosomal 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 potencyfor PDE5 approximately 50 % that of the parent drug. The N-desmethyl metabolite is furthermetabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterialhypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those ofsildenafil after 20 mg three times a day dosing (translating into a 36 % contribution to sildenafil’spharmacological effects). The subsequent effect on efficacy is unknown.

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

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting inapproximately 90 % higher plasma concentrations of sildenafil and the active N-desmethyl metabolitecompared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasmaprotein binding, the corresponding increase in free sildenafil plasma concentration was approximately40 %.

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

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) sildenafil clearancewas reduced, resulting in increases in AUC (85 %) and Cmax (47 %) compared to age-matchedvolunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and Cmax valueswere significantly increased by 154 % and 87 %, respectively in cirrhotic subjects compared tosubjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severelyimpaired hepatic function have not been studied.

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 Cmin compared to healthy volunteers. Both findings suggest a lowerclearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterialhypertension compared to healthy volunteers.

From the analysis of the pharmacokinetic profile of sildenafil in patients involved in the paediatricclinical trials, body weight was shown to be a good predictor of drug exposure in children. Sildenafilplasma concentration half-life values were estimated to range from 4.2 to 4.4 hours for a range of 10 to70 kg of body weight and did not show any differences that would appear as clinically relevant. Cmaxafter 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. Cmax after a single 10 mg sildenafil dose administered PO wasestimated at 24, 53 and 85 ng/ml for 70, 20 and 10 kg patients, respectively. Tmax was estimated atapproximately 1 hour and was almost independent from body weight.

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, toxicity toreproduction 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 wereapproximately fifty times the expected human exposure at 20 mg three times a day. Effects innon-clinical studies were observed at exposures considered sufficiently in excess of the maximumhuman exposure indicating little relevance to clinical use.

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

Microcrystalline cellulose

Calcium hydrogen phosphate (anhydrous)

Croscarmellose sodium

Magnesium stearate

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Glycerol triacetate

Not applicable.

5 years.

Do not store above 30°C. Store in the original package in order to protect from moisture.

PVC/Aluminium blisters of 90 tablets.

Pack size of 90 tablets in a carton.90 x 1 tablets in PVC/Aluminium perforated unit dose blisters.

PVC/Aluminium blisters of 300 tablets.

Pack size of 300 tablets in a carton.

Not all pack sizes may be marketed.

No special requirements for disposal.

Upjohn EESV

Rivium Westlaan 1422909 LD Capelle aan den IJssel

Netherlands

EU/1/05/318/001

EU/1/05/318/004

EU/1/05/318/005

Date of first authorisation: 28 October 2005

Date of latest renewal: 23 September 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu