Revatio

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 

Revatio 20 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

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

 

Excipient(s) with known effect 

Each tablet also contains 0.7 mg of lactose. 

For the full list of excipients, see section 6.1. 
 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 
 

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

 

 

4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 

 

Adults 

Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II 

and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension 

and pulmonary hypertension associated with connective tissue disease. 

 

Paediatric population 

Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. 

Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown 

in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart 

disease (see section 5.1). 

 

4.2 Posology and method of administration 
 
Treatment should only be initiated and monitored by a physician experienced in the treatment of 

pulmonary arterial hypertension. In case of clinical deterioration in spite of Revatio treatment, 

alternative therapies should be considered. 

 

Posology 

 
Adults 

The recommended dose is 20 mg three times a day (TID). Physicians should advise patients who 

forget to take Revatio to take a dose as soon as possible and then continue with the normal dose. 

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

 
Paediatric population (1 year to 17 years) 

For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is 10 mg 

three times a day and for patients > 20 kg is 20 mg three times a day. Higher than recommended doses 

should not be used in paediatric patients with PAH (see also sections 4.4 and 5.1). The 20 mg tablet 

should not be used in cases where 10 mg TID should be administered in younger patients. Other 

pharmaceutical forms are available for administration to patients ≤ 20 kg and other younger patients 

who are not able to swallow tablets. 

 



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Patients using other medicinal products 

In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A 

downward dose adjustment to 20 mg twice daily should be considered when sildenafil is 

co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A 
downward dose adjustment to 20 mg once daily is recommended in case of co-administration with 

more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone. For the use of 

sildenafil with the most potent CYP3A4 inhibitors, see section 4.3. Dose adjustments for sildenafil 

may be required when co-administered with CYP3A4 inducers (see section 4.5). 

 
Special populations 

 

Elderly (≥ 65 years) 

Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk 

distance could be less in elderly patients. 
 

Renal impairment 

Initial dose adjustments are not required in patients with renal impairment, including severe renal 

impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 20 mg twice daily 

should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated. 

 
Hepatic impairment 

Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and 

B). A downward dose adjustment to 20 mg twice daily should be considered after a careful 

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

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

section 4.3). 

 

Paediatric population (children less than 1 year and neonates) 

Outside its authorised indications, sildenafil should not be used in neonates with persistent pulmonary 

hypertension of the newborn as risks outweigh the benefits (see section 5.1). The safety and efficacy 

of Revatio in other conditions in children below 1 year of age has not been established. No data are 

available. 
 

Discontinuation of treatment 

Limited data suggest that the abrupt discontinuation of Revatio is not associated with rebound 

worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden 

clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified 
monitoring is recommended during the discontinuation period. 

 

Method of administration 

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

food. 

 

4.3 Contraindications 

 

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

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

hypotensive effects of nitrates (see section 5.1). 

 

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

4.5). 

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



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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. 

 

4.4 Special warnings and precautions for use 
 

The efficacy of Revatio has not been established in patients with severe pulmonary arterial 
hypertension (functional class IV). If the clinical situation deteriorates, therapies that are 

recommended at the severe stage of the disease (eg, epoprostenol) should be considered (see section 

4.2). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO 

functional class I pulmonary arterial hypertension. 

 
Studies with sildenafil have been performed in forms of pulmonary arterial hypertension related to 

primary (idiopathic), connective tissue disease associated or congenital heart disease associated forms 

of PAH (see section 5.1). The use of sildenafil in other forms of PAH is not recommended. 

 

In the long term paediatric extension study, an increase in deaths was observed in patients 
administered doses higher than the recommended dose. Therefore, doses higher than the recommended 

doses should not be used in paediatric patients with PAH (see also sections 4.2 and 5.1). 

 

Retinitis pigmentosa 

The safety of sildenafil has not been studied in patients with known hereditary degenerative retinal 
disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal 

phosphodiesterases) and therefore its use is not recommended. 

 

Vasodilatory action 

When prescribing sildenafil, physicians should carefully consider whether patients with certain 

underlying conditions could be adversely affected by sildenafil’s mild to moderate vasodilatory 
effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular 

outflow obstruction or autonomic dysfunction (see section 4.4). 

 

Cardiovascular risk factors 

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular 
events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, 

cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been 

reported in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-

existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual 

intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity. 
It is not possible to determine whether these events are related directly to these factors or to other 

factors. 

 

Priapism 

Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as 

angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may 
predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia). 

 

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In 

the event of an erection that persists longer than 4 hours, the patient should seek immediate medical 

assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency 
could result (see section 4.8). 



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Vaso-occlusive crises in patients with sickle cell anaemia 

Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell 

anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported 

more commonly by patients receiving Revatio than those receiving placebo leading to the premature 

termination of this study. 

 
Visual events 

Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil 

and other PDE5 inhibitors. Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, 

have been reported spontaneously and in an observational study in connection with the intake 

of sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual defect, the 
treatment should be stopped immediately and alternative treatment should be considered (see section 

4.3). 

 

Alpha-blockers 

Caution is advised when sildenafil is administered to patients taking an alpha-blocker as the 
co-administration may lead to symptomatic hypotension in susceptible individuals (see section 4.5). In 

order to minimise the potential for developing postural hypotension, patients should be 

haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians 

should advise patients what to do in the event of postural hypotensive symptoms. 

 

Bleeding disorders 
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium 

nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with 

bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these 

patients only after careful benefit-risk assessment. 

 
Vitamin K antagonists 

In pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding 

when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients 

with pulmonary arterial hypertension secondary to connective tissue disease. 

 
Veno-occlusive disease 

No data are available with sildenafil in patients with pulmonary hypertension associated with 

pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been 

reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should 

signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary 

hypertension, the possibility of associated veno-occlusive disease should be considered. 
 

Galactose intolerance 

Lactose monohydrate is present in the tablet film coat. Patients with rare hereditary problems of 

galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take 

this medicine. 
 

Use of sildenafil with bosentan 

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

demonstrated (see sections 4.5 and 5.1). 

 
Concomitant use with other PDE5 inhibitors 

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, 

including Viagra, has not been studied in PAH patients and such concomitant use is not recommended 

(see section 4.5). 

 



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4.5 Interaction with other medicinal products and other forms of interaction 
 

Effects of other medicinal products on sildenafil 

 

In vitro studies 

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major 
route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil 

clearance and inducers of these isoenzymes may increase sildenafil clearance. For dose 

recommendations, see sections 4.2 and 4.3. 

 

In vivo studies  

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

and 5.1). 

 

The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial 

hypertension (eg, ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, 

caution is recommended in case of co-administration. 

 

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been 

studied in pulmonary arterial hypertension patients (see section 4.4). 

 

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a 
reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with 

CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the 

only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with 

pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and 

CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients 
not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg 

three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration 

range covers the increase in sildenafil exposure observed in specifically designed drug interaction 

studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, 

ketoconazole, itraconazole, ritonavir). 
 

CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in 

pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with 

CYP3A4 inducer bosentan. 

 

Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 
125 mg twice daily with sildenafil 80 mg three times a day (at steady state) concomitantly 

administered during 6 days in healthy volunteers resulted in a 63 % decrease of sildenafil AUC. A 

population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials 

including a 12 week study to assess the efficacy and safety of oral sildenafil 20 mg three times a day 

when added to a stable dose of bosentan (62.5 mg – 125 mg twice a day) indicated a decrease in 
sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see 

sections 4.4 and 5.1). 

  

Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 

inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine. 
 

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at 

steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300 % (4-fold) 

increase in sildenafil Cmax and a 1,000 % (11-fold) increase in sildenafil plasma AUC. At 24 hours, the 

plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml 

when sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broad 
range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with 

ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3). 

 



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Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state 
(1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140 % increase in 

sildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir 

pharmacokinetics. For dose recommendations, see section 4.2. 

 

When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 

inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in sildenafil 
systemic exposure (AUC). For dose recommendations, see section 4.2. In healthy male volunteers, 

there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, 

elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite. 

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

CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil concentrations when co-administered 
with sildenafil (50 mg) to healthy volunteers. No dose adjustment is required. 

 

The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected 

to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, 

telithromycin and nefazodone are expected to have an effect in between that of ritonavir and CYP3A4 
inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. Therefore 

dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2). 

 

The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that 

co-administration of beta-blockers in combination with CYP3A4 substrates might result in an 

additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone. 
 

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest 

increases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use of 

sildenafil and grapefruit juice is not recommended. 

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

of sildenafil. 

 

Co-administration of oral contraceptives (ethinyloestradiol 30 g and levonorgestrel 150 g) did not 

affect the pharmacokinetics of sildenafil. 
 

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has 

the potential to have serious interaction with sildenafil (see section 4.3). 

 

Effects of sildenafil on other medicinal products 

 

In vitro studies 

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 

(IC50 > 150 M).   

 

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

 

In vivo studies 

No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide 

(250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9. 
 

Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that 

sildenafil does not have a clinically relevant effect on CYP3A4. 

 

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

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

(150 mg). 



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Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with 

mean maximum blood alcohol levels of 80 mg/dl. 

 

In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50 % 

increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from a 

study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) indicated 
an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with co-administration of steady-state 

sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-

administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1). 

 

In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in 
hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. 

The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These 

additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was 

administered alone to healthy volunteers. 

 
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and 

sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign 

prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean 

additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 

8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg, 

11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were 
administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports 

of patients who experienced symptomatic postural hypotension. These reports included dizziness and 

lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking 

alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 

4.4). 
 

Sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease 

inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor. 

 

Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was 
shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide 

donors or nitrates in any form is therefore contraindicated (see section 4.3).  

 

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 

inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the 

hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the 

combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including 

sildenafil, is contraindicated (see section 4.3). 
 

Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives 

(ethinyloestradiol 30 g and levonorgestrel 150 g). 

 

Paediatric population 

Interaction studies have only been performed in adults. 

 

4.6 Fertility, pregnancy and lactation 

 

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. 

 



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Pregnancy 
There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct 

or indirect harmful effects with respect to pregnancy and embryonal/foetal development. Studies in 

animals have shown toxicity with respect to postnatal development (see section 5.3).  

 

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

 
Breast-feeding 

There are no adequate and well controlled studies in lactating women. Data from one lactating woman 

indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk at 

very low levels. No clinical data are available regarding adverse events in breast-fed infants, but 

amounts ingested would not be expected to cause any adverse effects. Prescribers should carefully 
assess the mother’s clinical need for sildenafil and any potential adverse effects on the breast-fed 

child. 

 

Fertility 

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

section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

Revatio has moderate influence on the ability to drive and use machines. 

 

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware 

of how they might be affected by Revatio, before driving or using machines. 

 
4.8 Undesirable effects 

 

Summary of the safety profile 

In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 

207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg TID doses of Revatio and 
70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall 

frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID 

was 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the 277 subjects treated 

in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day 

(4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 % 

of 183 patients on study treatment were receiving Revatio 80 mg TID. 
 

In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary 

arterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting from 

20 mg, to 40 mg and then 80 mg, three times a day, as tolerated) and epoprostenol, and 131 patients 

were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall 
frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 

5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse 

reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular 

hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known 

adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency 
in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the 

subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg 

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

Revatio 80 mg TID. 

 
In the twoplacebo-controlled studies adverse events were generally mild to moderate in severity. The 

most commonly reported adverse reactions that occurred (greater or equal to 10 %) on Revatio 

compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity. 

 



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Tabulated list of adverse reactions 

Adverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 % 

difference) on Revatio in the pivotal study or in the Revatio combined data set of both the 

placebo-controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg TID are 

listed in the table below by class and frequency grouping (very common ( 1/10), common ( 1/100 to 

< 1/10), uncommon ( 1/1000 to < 1/100) and not known (cannot be estimated from the available 

data). Within each frequency grouping, adverse reactions are presented in order of decreasing 

seriousness. 

 

Reports from post-marketing experience are included in italics. 

 

MedDRA system organ class (V.14.0) Adverse reaction 

Infections and infestations  

Common 

 

cellulitis, influenza, bronchitis, 

sinusitis, rhinitis, gastroenteritis 

Blood and lymphatic system disorders  

Common anaemia 

Metabolism and nutrition disorders  

Common fluid retention 

Psychiatric disorders  

Common insomnia, anxiety 

Nervous system disorders  

Very common headache  

Common migraine, tremor, paraesthesia, burning 

sensation, hypoaesthesia 

Eye disorders  

Common retinal haemorrhage, visual 

impairment, vision blurred, 

photophobia, chromatopsia, cyanopsia, 

eye irritation, ocular hyperaemia 

Uncommon visual acuity reduced, diplopia, 

abnormal sensation in eye 

Not known Non-arteritic anterior ischaemic optic 

neuropathy (NAION)*, Retinal 

vascular occlusion*, Visual field 

defect* 

Ear and labyrinth disorders  

Common vertigo 

Not known sudden hearing loss 

Vascular disorders  

Very common flushing 

Not Known hypotension 

Respiratory, thoracic and mediastinal disorders  

Common epistaxis, cough, nasal congestion  

Gastrointestinal disorders  

Very common diarrhoea, dyspepsia  

Common gastritis, gastrooesophageal reflux 

disease, haemorrhoids, abdominal 

distension, dry mouth 

Skin and subcutaneous tissue disorders  

Common alopecia, erythema, night sweats 

Not known rash 

Musculoskeletal and connective tissue disorders  

Very common pain in extremity 

Common myalgia, back pain  



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Renal and urinary disorders  

Uncommon haematuria 

Reproductive system and breast disorders   

Uncommon penile haemorrhage, haematospermia, 

gynaecomastia 

Not known priapism, erection increased 

General disorders and administration site 

conditions 

 

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

 

Paediatric population 

In the placebo-controlled study of Revatio in patients 1 to 17 years of age with pulmonary arterial 

hypertension, a total of 174 patients were treated three times a day with either low (10 mg in patients 
> 20 kg; no patients ≤ 20 kg received the low dose), medium (10 mg in patients ≥ 8-20 kg; 20 mg in 

patients ≥ 20-45 kg; 40 mg in patients > 45 kg) or high dose (20 mg in patients ≥ 8-20 kg; 40 mg in 

patients ≥ 20-45 kg; 80 mg in patients > 45 kg) regimens of Revatio and 60 were treated with placebo.   

 

The adverse reactions profile seen in this paediatric study was generally consistent with that in adults 

(see table above). The most common adverse reactions that occurred (with a frequency ≥ 1 %) in 

Revatio patients (combined doses) and with a frequency > 1 % over placebo patients were pyrexia, 

upper respiratory tract infection (each 11.5%), vomiting (10.9%), erection increased (including 
spontaneous penile erections in male subjects) (9.0%), nausea, bronchitis (each 4.6%), pharyngitis 

(4.0%), rhinorrhoea (3.4%), and pneumonia, rhinitis (each 2.9%). 

 

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered 

the long-term extension study. Subjects on active sildenafil therapy continued on the same treatment 
regimen, while those in the placebo group in the short-term study were randomly reassigned to 

sildenafil treatment. 

 

The most common adverse reactions reported across the duration of the short-term and long-term 

studies were generally similar to those observed in the short-term study. Adverse reactions reported in 
>10% of 229 subjects treated with sildenafil (combined dose group, including 9 patients that did not 

continue into the long-term study) were upper respiratory infection (31%), headache (26%), vomiting 

(22%), bronchitis (20%), pharyngitis (18%), pyrexia (17%), diarrhoea (15%), and influenza, epistaxis 

(12% each). Most of these adverse reactions were considered mild to moderate in severity. 

 
Serious adverse events were reported in 94 (41%) of the 229 subjects receiving sildenafil. Of the 94 

subjects reporting a serious adverse event, 14/55 (25.5%) subjects were in the low dose group, 35/74 

(47.3%) in the medium dose group, and 45/100 (45%) in the high dose group. The most common 

serious adverse events that occurred with a frequency ≥ 1 % in sildenafil patients (combined doses) 

were pneumonia (7.4%), cardiac failure, pulmonary hypertension (each 5.2%), upper respiratory tract 

infection (3.1%), right ventricular failure, gastroenteritis (each 2.6%), syncope, bronchitis, 
bronchopneumonia, pulmonary arterial hypertension (each 2.2%), chest pain, dental caries (each 

1.7%), and cardiogenic shock, gastroenteritis viral, urinary tract infection (each 1.3%). 

 

The following serious adverse events were considered to be treatment related, enterocolitis, 

convulsion, hypersensitivity, stridor, hypoxia, neurosensory deafness and ventricular arrhythmia. 
 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 



12 

4.9 Overdose 
 

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at 

lower doses, but the incidence rates and severities were increased. At single doses of 200 mg the 

incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, and altered 

vision) was increased. 

 
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is 

not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated 

in the urine. 

 

 
5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

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

Mechanism of action 

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific 

phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart from 

the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the 

pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth 
muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to 

vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic 

circulation. 

 

Pharmacodynamic effects 
Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 

than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved 

in the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over 

700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold 

selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control 
of cardiac contractility. 

 

Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of 

cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients 

with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was 

a decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a day 
to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were 

observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 

20 mg three times a day no reductions in systolic or diastolic pressure were seen. 

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant 

effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial 
hypertension no clinically relevant effects on the ECG were reported. 

 

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with 

severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean 

resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to 
baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on 

cardiac output, and did not impair blood flow through the stenosed coronary arteries.  

 

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 



13 

with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) 
demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour 

discrimination simulated traffic light, Humphrey perimeter and photostress). 

 

Clinical efficacy and safety 

 

Efficacy in adult patients with pulmonary arterial hypertension (PAH) 

A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary 

pulmonary hypertension, PAH associated with connective tissue disease, and PAH following surgical 

repair of congenital heart lesions. Patients were randomised to one of four treatment groups: placebo, 

sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients 

randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 

68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline 

6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients 

(63 %) included were diagnosed with primary pulmonary hypertension, 84 (30 %) were diagnosed 

with PAH associated with connective tissue disease and 18 (7 %) of the patients were diagnosed with 

PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional Class 

II (107/277, 39 %) or III (160/277, 58 %) with a mean baseline 6 minute walking distance of 

378 meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4 %) or IV (9/277, 3 %) 

at baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening fraction 

< 0.2 were not studied. 

 

Sildenafil (or placebo) was added to patients’ background therapy which could have included a 
combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of 

prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on 

therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy 

were excluded from the study. 

 

The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance 
(6MWD). A statistically significant increase in 6MWD was observed in all 3 sildenafil dose groups 

compared to those on placebo. Placebo corrected increases in 6MWD were 45 metres (p < 0.0001), 

46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID 

respectively. There was no significant difference in effect between sildenafil doses.  For patients with a 

baseline 6MWD < 325 m improved efficacy was observed with higher doses (placebo-corrected 
improvements of 58 metres, 65 metres and 87 metres for 20 mg, 40 mg and 80 mg doses TID, 

respectively). 

 

When analysed by WHO functional class, a statistically significant increase in 6MWD was observed 

in the 20 mg dose group. For class II and class III, placebo corrected increases of 49 metres 
(p = 0.0007) and 45 metres (p = 0.0031) were observed respectively. 

 

The improvement in 6MWD was apparent after 4 weeks of treatment and this effect was maintained at 

weeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary and 

connective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAP 

and PVRI. 
 

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial 

pressure (mPAP) and pulmonary vascular resistance (PVR) compared to those on placebo. Placebo-

corrected treatment effects with mPAP were –2.7 mmHg (p = 0.04), -3.0 mm Hg (p = 0.01) and 

-5.1 mm Hg (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID respectively. Placebo-corrected 
treatment effects with PVR were -178 dyne.sec/cm5 (p=0.0051), -195 dyne.sec/cm5 (p=0.0017) and 

-320 dyne.sec/cm5 (p<0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID, respectively. The percent 

reduction at 12 weeks for sildenafil 20 mg, 40 mg and 80 mg TID in PVR (11.2 %, 12.9 %, 23.3 %) 

was proportionally greater than the reduction in systemic vascular resistance (SVR) (7.2 %, 5.9 %, 

14.4 %). The effect of sildenafil on mortality is unknown. 
 



14 

A greater percentage of patients on each of the sildenafil doses (i.e. 28 %, 36 % and 42 % of subjects 
who received sildenafil 20 mg, 40 mg and 80 mg TID doses, respectively) showed an improvement by 

at least one WHO functional class at week 12 compared to placebo (7 %). The respective odds ratios 

were 2.92 (p=0.0087), 4.32 (p=0.0004) and 5.75 (p<0.0001). 

 

Long-term survival data in naive population 

Patients enrolled into the pivotal study were eligible to enter a long term open label extension study. 

At 3 years 87 % of the patients were receiving a dose of 80 mg TID. A total of 207 patients were 

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

A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who 

were stabilised on intravenous epoprostenol. The PAH patients included those with Primary 

Pulmonary Arterial Hypertension (212/267, 79 %) and PAH associated with connective tissue disease 

(55/267, 21 %). Most patients were WHO Functional Class II (68/267, 26 %) or III (175/267, 66 %); 

fewer patients were Class I (3/267, 1 %) or IV (16/267, 6 %) at baseline; for a few patients (5/267, 

2 %), the WHO Functional Class was unknown. Patients were randomised to placebo or sildenafil (in 

a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) when 

used in combination with intravenous epoprostenol. 

 

The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance. 

There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk 

distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of 
sildenafil (95 % CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance 

≥ 325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline 

walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients 

with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with PAH 

associated with connective tissue disease. The difference in results between these randomisation 
subgroups may have arisen by chance in view of their limited sample size. 

 

Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial 

Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of 

-3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time to clinical 

worsening was a secondary endpoint as defined as the time from randomisation to the first occurrence 

of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical 

deterioration requiring a change in epoprostenol therapy). Treatment with sildenafil significantly 

delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects 

experienced clinical worsening events in the placebo group (17.6 %) compared with 8 subjects in the 

sildenafil group (6.0 %). 

 

Long-term Survival Data in the background epoprostenol study 

Patients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term open 

label extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg TID. A total of 

134 patients were treated with Revatio in the initial study, and their long term survival status was 

assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year 

survival were 92 %, 81 % and 74 %, respectively. 

 

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

A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjects 

with PAH (WHO FC II and III) who were on bosentan therapy for a minimum of three months. The 

PAH patients included those with primary PAH, and PAH associated with connective tissue disease. 

Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with 



15 

bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at 

Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from 

baseline on 6MWD observed between sildenafil (20 mg three times a day) and placebo (13.62 m (95% 

CI: -3.89 to 31.12) and 14.08 m (95% CI: -1.78 to 29.95), respectively). 

 

Differences in 6MWD were observed between patients with primary PAH and PAH associated with 

connective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baseline 

were 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52) for the sildenafil and 

placebo groups, respectively. However, for subjects with PAH associated with connective tissue 

disease (36 subjects) mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and 

17.50 m (95% CI: -9.41 to 44.41) for the sildenafil and placebo groups, respectively. 

 

Overall, the adverse events were generally similar between the two treatment groups (sildenafil plus 

bosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used as 

monotherapy (see sections 4.4 and 4.5). 

 

Paediatric population 

 

Pulmonary arterial hypertension 

 

A total of 234 subjects aged 1 to 17 years were treated in a randomized, double-blind, multi-centre, 

placebo controlled parallel group, dose ranging study. Subjects (38 % male and 62 % female) had a 

body weight  8 kg, and had primary pulmonary hypertension (PPH) [33 %], or PAH secondary to 

congenital heart disease [systemic-to-pulmonary shunt 37 %, surgical repair 30 %]. In this trial, 63 of 

234 (27 %) patients were < 7 years old (sildenafil low dose = 2; medium dose = 17; high dose = 28; 

placebo = 16) and 171 of 234 (73 %) patients were 7 years or older (sildenafil low dose = 40; medium 

dose = 38; and high dose = 49; placebo = 44). Most subjects were WHO Functional Class I 

(75/234, 32 %) or II (120/234, 51 %) at baseline; fewer patients were Class III (35/234, 15 %) or IV 

(1/234, 0.4 %); for a few patients (3/234, 1.3 %), the WHO Functional Class was unknown. 

 

Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and 

endothelin receptor antagonists was not permitted in the study, and neither was arginine 

supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors. 

 

The primary objective of the study was to assess the efficacy of 16 weeks of chronic treatment with 

oral sildenafil in paediatric subjects to improve exercise capacity as measured by the Cardiopulmonary 

Exercise Test (CPET) in subjects who were developmentally able to perform the test, n = 115). 

Secondary endpoints included haemodynamic monitoring, symptom assessment, WHO functional 

class, change in background treatment, and quality of life measurements. 

 

Subjects were allocated to one of three sildenafil treatment groups, low (10 mg), medium (10-40 mg) 

or high dose (20-80 mg) regimens of Revatio given three times a day, or placebo. Actual doses 

administered within a group were dependent on body weight (see Section 4.8). The proportion of 

subjects receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel 

blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (47.7 %) and 

the placebo treatment group (41.7 %). 

 

The primary endpoint was the placebo-corrected percentage change in peak VO2 from baseline to 

week 16 assessed by CPET 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 and 

developmentally able to perform the test. Children < 7 years (sildenafil combined dose = 47; placebo = 

16) were evaluable only for the secondary endpoints. Mean baseline peak volume of oxygen 

consumed (VO2) values were comparable across the sildenafil treatment groups (17.37 to 

18.03 ml/kg/min), and slightly higher for the placebo treatment group (20.02 ml/kg/min). The results 

of the main analysis (combined dose groups versus placebo) were not statistically significant 



16 

(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 

(n=24) 

3.81 

 

-6.11, 13.73 

Medium dose 

(n=26) 

11.33 

 

1.72, 20.94 

High dose 

(n=27) 

7.98 

 

-1.64, 17.60 

Combined dose groups 
(n=77) 

7.71 
(p = 0.056) 

-0.19, 15.60 

n=29 for placebo group 

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

weight group 

 

Dose related improvements were observed with pulmonary vascular resistance index (PVRI) and mean 

pulmonary arterial pressure (mPAP). The sildenafil medium and high dose groups both showed PVRI 

reductions compared to placebo, of 18 % (95 % CI: 2 % to 32 %) and 27 % (95 % CI: 14 % to 39 %), 

respectively; whilst the low dose group showed no significant difference from placebo (difference of 

2 %). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared 

to placebo, of -3.5 mmHg (95 % CI: -8.9, 1.9) and -7.3 mmHg (95 % CI: -12.4, -2.1), respectively; 

whilst the low dose group showed little difference from placebo (difference of 1.6 mmHg). 

Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10 %, 

4 % and 15 % for the low, medium and high dose groups respectively. 

 

Significant improvements in functional class were demonstrated only in subjects on sildenafil high 

dose compared to placebo. Odds ratios for the sildenafil low, medium and high dose groups compared 

to placebo were 0.6 (95 % CI: 0.18, 2.01), 2.25 (95 % CI: 0.75, 6.69) and 4.52 (95 % CI: 1.56, 13.10), 

respectively. 

 

Long term extension data 

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered 

the long-term extension study. Subjects who had been in the placebo group in the short-term study 

were randomly reassigned to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium or 

high dose groups (1:1), while subjects weighing > 20 kg entered the low, medium or high dose groups 
(1:1:1). Of the total 229 subjects who received sildenafil, there were 55, 74, and 100 subjects in the 

low, medium and high dose groups, respectively. Across the short-term and long-term studies, the 

overall duration of treatment from start of double-blind for individual subjects ranged from 

3 to 3129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1696 days 

(excluding the 5 subjects who received placebo in double-blind and were not treated in the long-term 
extension study). 

 
Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94 %, 

93 % and 85 % in the low, medium and high dose groups, respectively; for patients ≤ 20 kg in weight 

at baseline, the survival estimates were 94 % and 93 % for subjects in the medium and high dose 

groups respectively (see sections 4.4 and 4.8). 

 

During the conduct of the study, there were a total of 42 deaths reported, whether on treatment or 

reported as part of the survival follow-up. 37 deaths occurred prior to a decision taken by the Data 
Monitoring Committee to down titrate subjects to a lower dosage, based on an observed mortality 

imbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was 

5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, 

respectively. An additional 5 deaths were reported subsequently.The causes of deaths were related to 



17 

PAH. Higher than recommended doses should not be used in paediatric patients with PAH (see 
sections 4.2 and 4.4). 

 

Peak VO2 was assessed 1 year after the start of the placebo-controlled study. Of those sildenafil treated 

subjects developmentally able to perform the CPET 59/114 subjects (52 %) had not shown any 

deterioration in Peak VO2 from start of sildenafil. Similarly 191 of 229 subjects (83 %) who had 

received sildenafil had either maintained or improved their WHO Functional Class at 1 year 

assessment. 

 

Persistent pulmonary hypertension of the newborn 

 

A randomized, double-blind, two-arm, parallel-group, placebo-controlled study was conducted in 

59 neonates with persistent pulmonary hypertension of the newborn (PPHN), or hypoxic respiratory 

failure (HRF) and at risk for PPHN with oxygenation index (OI) >15 and <60. The primary objective 

was 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 treatment 

targeting 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. The 

difference 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). For 

patients without treatment failure, the mean time on iNO treatment after initiation of IV study drug 

was 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%) and 

7 (24.1%) subjects in the iNO + IV sildenafil treatment group, respectively, and in 19 (63.3%) and 

2 (6.7%) subjects in the iNO + placebo group, respectively. The most commonly reported 

treatment-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). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 

120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral 
bioavailability is 41 % (range 25-63 %). After oral three times a day dosing of sildenafil, AUC and 

Cmax increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg three 

times a day a more than dose proportional increase in sildenafil plasma levels has been observed. In 

pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg three times a 

day was on average 43 % (90 % CI: 27 % - 60 %) higher compared to the lower doses.  
 

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in Tmax of 

60 minutes and a mean reduction in Cmax of 29 % however, the extent of absorption was not 

significantly affected (AUC decreased by 11 %). 

 
Distribution 

The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into 

the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration 

of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N-

desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding is 

independent of total drug concentrations. 
 



18 

Biotransformation 
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic 

microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. 

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

for PDE5 approximately 50 % that of the parent drug. The N-desmethyl metabolite is further 

metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial 

hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those of 
sildenafil after 20 mg three times a day dosing (translating into a 36 % contribution to sildenafil’s 

pharmacological effects). The subsequent effect on efficacy is unknown. 

 

Elimination 

The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3-5 h. After 
either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the 

faeces (approximately 80 % of administered oral dose) and to a lesser extent in the urine 

(approximately 13 % of administered oral dose). 

 

Pharmacokinetics in special patient groups 

 

Elderly 

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in 
approximately 90 % higher plasma concentrations of sildenafil and the active N-desmethyl metabolite 

compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma 

protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 

40 %. 

 
Renal insufficiency 

In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml/min), the 

pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. In volunteers 

with severe renal impairment (creatinine clearance < 30 ml/min), sildenafil clearance was reduced, 

resulting in mean increases in AUC and Cmax of 100 % and 88 % respectively compared to 
age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax 

values were significantly increased by 200 % and 79 % respectively in subjects with severe renal 

impairment compared to subjects with normal renal function. 

 

Hepatic insufficiency 

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) sildenafil clearance 
was reduced, resulting in increases in AUC (85 %) and Cmax (47 %) compared to age-matched 

volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and Cmax values 

were significantly increased by 154 % and 87 %, respectively in cirrhotic subjects compared to 

subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely 

impaired hepatic function have not been studied. 
 

Population pharmacokinetics 

In patients with pulmonary arterial hypertension, the average steady state concentrations were 20-50 % 

higher over the investigated dose range of 20–80 mg three times a day compared to healthy volunteers. 

There was a doubling of the Cmin compared to healthy volunteers. Both findings suggest a lower 
clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterial 

hypertension compared to healthy volunteers. 

 

Paediatric population 

From the analysis of the pharmacokinetic profile of sildenafil in patients involved in the paediatric 

clinical trials, body weight was shown to be a good predictor of drug exposure in children. Sildenafil 

plasma concentration half-life values were estimated to range from 4.2 to 4.4 hours for a range of 10 to 

70 kg of body weight and did not show any differences that would appear as clinically relevant. Cmax 
after a single 20 mg sildenafil dose administered PO was estimated at 49, 104 and 165 ng/ml for 70, 

20 and 10 kg patients, respectively. Cmax after a single 10 mg sildenafil dose administered PO was 



19 

estimated at 24, 53 and 85 ng/ml for 70, 20 and 10 kg patients, respectively. Tmax was estimated at 
approximately 1 hour and was almost independent from body weight. 

 

5.3 Preclinical safety data 

 

Non-clinical data revealed no special hazard for humans based on conventional studies of safety 

pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, toxicity to 
reproduction and development. 

 

In pups of rats which were pre- and postnatally treated with 60 mg/kg sildenafil, a decreased litter size, 

a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were 

approximately fifty times the expected human exposure at 20 mg three times a day. Effects in 
non-clinical studies were observed at exposures considered sufficiently in excess of the maximum 

human exposure indicating little relevance to clinical use. 

 

There were no adverse reactions, with possible relevance to clinical use, seen in animals at clinically 

relevant exposure levels which were not also observed in clinical studies. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Tablet core: 

Microcrystalline cellulose 

Calcium hydrogen phosphate (anhydrous) 

Croscarmellose sodium 
Magnesium stearate 

 

Film coat: 

Hypromellose 

Titanium dioxide (E171) 

Lactose monohydrate 
Glycerol triacetate 

 

6.2 Incompatibilities 

 

Not applicable. 
 

6.3 Shelf life 

 

5 years. 

 
6.4 Special precautions for storage 

 

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

 

6.5 Nature and contents of container 
 

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. 



20 

 
6.6  Special precautions for disposal and other handling 

 

No special requirements for disposal. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Upjohn EESV 

Rivium Westlaan 142 

2909 LD Capelle aan den IJssel 

Netherlands 
 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/05/318/001 
EU/1/05/318/004 

EU/1/05/318/005 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 
Date of first authorisation: 28 October 2005 

Date of latest renewal: 23 September 2010 

 

 

10. DATE OF REVISION OF THE TEXT 

 

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

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



21 

1. NAME OF THE MEDICINAL PRODUCT 

 

Revatio 0.8 mg/ml solution for injection 

 
 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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). 
 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Solution for injection. 

Clear, colourless solution. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 

 

Revatio solution for injection is for the treatment of adult patients (≥ 18 years) with pulmonary arterial 

hypertension who are currently prescribed oral Revatio and who are temporarily unable to take oral 
therapy, but are otherwise clinically and haemodynamically stable. 

 

Revatio (oral) is indicated for treatment of adult patients with pulmonary arterial hypertension 

classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown 

in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue 
disease. 

 

4.2 Posology and method of administration 

 

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. 
 

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

 

Posology 

 
Adults 

The recommended dose is 10 mg (corresponding to 12.5 ml) three times a day administered as an 

intravenous bolus injection (see section 6.6). 

 

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

 

Patients using other medicinal products 

In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A 

downward dose adjustment to 10 mg twice daily should be considered when sildenafil is 

co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A 



22 

downward dose adjustment to 10 mg once daily is recommended in case of co-administration with 
more potent CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone. For the use of 

sildenafil with the most potent CYP3A4 inhibitors, see section 4.3. Dose adjustments for sildenafil 

may be required when co-administered with CYP3A4 inducers (see section 4.5). 

 

Special populations 

 
Elderly (≥ 65 years) 

Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk 

distance could be less in elderly patients. 

 

Renal impairment 
Initial dose adjustments are not required in patients with renal impairment, including severe renal 

impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 10 mg twice daily 

should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated. 

 

Hepatic impairment 
Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A 

and B). A downward dose adjustment to 10 mg twice daily should be considered after a careful 

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

 

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

section 4.3). 
 

Paediatric population 

Revatio solution for injection is not recommended for use in children below 18 years due to 

insufficient data on safety and efficacy. Outside its authorised indications, sildenafil should not be 

used in neonates with persistent pulmonary hypertension of the newborn as risks outweigh the benefits 
(see section 5.1). 

 

Discontinuation of treatment 

Limited data suggest that the abrupt discontinuation of oral Revatio is not associated with rebound 

worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden 
clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified 

monitoring is recommended during the discontinuation period. 

 

Method of administration 

Revatio solution for injection is for intravenous use as a bolus injection.  

See section 6.6 for instructions of use. 

 

4.3 Contraindications 
 

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

 

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

hypotensive effects of nitrates (see section 5.1). 
 

The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, 

such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 

4.5). 

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

(see section 4.5). 

 

Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic 

neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 

inhibitor exposure (see section 4.4). 



23 

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

therefore contraindicated: 

Severe hepatic impairment, 

Recent history of stroke or myocardial infarction, 

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

 
4.4 Special warnings and precautions for use 

 

No clinical data is available for sildenafil IV administration in patients who are clinically or 

haemodynamically unstable. Its use is accordingly not recommended in these patients. 

 
The 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. 
 

Vasodilatory action 

When prescribing sildenafil, physicians should carefully consider whether patients with certain 

underlying conditions could be adversely affected by sildenafil’s mild to moderate vasodilatory 

effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular 
outflow obstruction or autonomic dysfunction (see section 4.4) 

 

Cardiovascular risk factors 

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular 

events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, 

cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been 
reported in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-

existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual 

intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity. 

It is not possible to determine whether these events are related directly to these factors or to other 

factors. 
 

Priapism 

Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as 

angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may 

predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).  
 

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In 

the event of an erection that persists longer than 4 hours, the patient should seek immediate medical 

assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency 

could result (see section 4.8). 
 



24 

Vaso-occlusive crises in patients with sickle cell anaemia 
Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell 

anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported 

more commonly by patients receiving Revatio than those receiving placebo leading to the premature 

termination of this study. 

 

Visual events 
Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil 

and other PDE5 inhibitors. Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, 

have been reported spontaneously and in an observational study in connection with the intake 

of sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual defect, the 

treatment should be stopped immediately and alternative treatment should be considered (see section 
4.3). 

 

Alpha-blockers 

Caution is advised when sildenafil is administered to patients taking an alpha-blocker as the 

co-administration may lead to symptomatic hypotension in susceptible individuals (see section 4.5). In 
order to minimise the potential for developing postural hypotension, patients should be 

haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians 

should advise patients what to do in the event of postural hypotensive symptoms.  

 

Bleeding disorders 

Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium 
nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with 

bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these 

patients only after careful benefit-risk assessment. 

 

Vitamin K antagonists 
In pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding 

when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients 

with pulmonary arterial hypertension secondary to connective tissue disease. 

 

Veno-occlusive disease 
No data are available with sildenafil in patients with pulmonary hypertension associated with 

pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been 

reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should 

signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary 

hypertension, the possibility of associated veno-occlusive disease should be considered. 

 
Use of sildenafil with bosentan 

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

demonstrated (see sections 4.5 and 5.1). 

 

Concomitant use with other PDE5 inhibitors 
The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, 

including Viagra, has not been studied in PAH patients and such concomitant use is not recommended 

(see section 4.5). 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

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. 

 



25 

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, ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, 

caution is recommended in case of co-administration. 

 

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been 

studied in pulmonary arterial hypertension patients (see section 4.4). 

 

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a 
reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with 

CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the 

only factors with a statistically significant impact on oral sildenafil pharmacokinetics in patients with 

pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and 

CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients 

not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at an oral dose of 
80 mg three times a day compared to the exposure at an oral dose of 20 mg three times a day. This 

concentration range covers the increase in sildenafil exposure observed in specifically designed drug 

interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, 

ketoconazole, itraconazole, ritonavir). 

 
CYP3A4 inducers seemed to have a substantial impact on the oral pharmacokinetics of sildenafil in 

pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with 

CYP3A4 inducer bosentan. 

 

Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 
125 mg twice daily with oral sildenafil 80 mg three times a day (at steady state) concomitantly 

administered during 6 days in healthy volunteers resulted in a 63 % decrease of sildenafil AUC. A 

population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials 

including a 12 week study to assess the efficacy and safety of oral sildenafil 20 mg three times a day 

when added to a stable dose of bosentan (62.5 mg – 125 mg twice a day) indicated a decrease in 

sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see 
sections 4.4 and 5.1). 

 

Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 

inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine.  

 
Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at 

steady state (500 mg twice daily) with oral sildenafil (100 mg single dose) resulted in a 300 % (4-fold) 

increase in sildenafil Cmax and a 1,000 % (11-fold) increase in sildenafil plasma AUC. At 24 hours, the 

plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml 



26 

when sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broad 
range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with 

ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3). 

 

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state 

(1200 mg three times a day) with oral sildenafil (100 mg single dose) resulted in a 140 % increase in 

sildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir 
pharmacokinetics. For dose recommendations, see section 4.2. 

 

When a single 100 mg dose of oral sildenafil was administered with erythromycin, a moderate 

CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in 

sildenafil systemic exposure (AUC). For dose recommendations, see section 4.2. In healthy male 
volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, 

Cmax, Tmax, elimination rate constant, or subsequent half-life of oral sildenafil or its principal 

circulating metabolite. No dose adjustment is required. Cimetidine (800 mg), a cytochrome P450 

inhibitor and a non-specific CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil 

concentrations when co-administered with oral sildenafil (50 mg) to healthy volunteers. No dose 
adjustment is required. 

 

The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected 

to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, 

telithromycin and nefazodone) are expected to have an effect in between that of ritonavir and CYP3A4 

inhibitors like saquinavir or erythromycin), a seven-fold increase in exposure is assumed. Therefore 
dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2). 

 

The population pharmacokinetic analysis in pulmonary arterial hypertension patients receiving oral 

sildenafil suggested that co-administration of beta-blockers in combination with CYP3A4 substrates 

might result in an additional increase in sildenafil exposure compared with administration of CYP3A4 
substrates alone. 

 

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest 

increases in plasma levels of oral sildenafil. No dose adjustment is required but the concomitant use of 

sildenafil and grapefruit juice is not recommended. 
 

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

bioavailability of sildenafil. 

 

Co-administration of oral contraceptives (ethinyloestradiol 30 g and levonorgestrel 150 g) 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 M). 

 
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. 

 



27 

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

 

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

 

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

(150 mg). 
 

Oral sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with 

mean maximum blood alcohol levels of 80 mg/dl. 

 

In a study of healthy volunteers oral sildenafil at steady state (80 mg three times a day) resulted in a 
50 % increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data 

from a study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) 

indicated an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with co-administration of steady-

state sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy volunteers when 

co-administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1). 
 

In a specific interaction study, where oral sildenafil (100 mg) was co-administered with amlodipine in 

hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. 

The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These 

additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was 

administered alone to healthy volunteers. 
 

In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and oral 

sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign 

prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean 

additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 
8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg, 

11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were 

administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports 

of patients who experienced symptomatic postural hypotension. These reports included dizziness and 

lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking 
alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 

4.4). 

 

Sildenafil (100 mg single oral dose) did not affect the steady state pharmacokinetics of the HIV 

protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.  

 
Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was 

shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide 

donors or nitrates in any form is therefore contraindicated (see section 4.3).  

 

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 
inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the 

hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the 

combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including 

sildenafil, is contraindicated (see section 4.3). 

 
Oral sildenafil had no clinically significant impact on the plasma levels of oral contraceptives 

(ethinyloestradiol 30 g and levonorgestrel 150 g). 

 

Paediatric population 

Interaction studies have only been performed in adults. 

 



28 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential and contraception in males and females 

Due to lack of data on effects of Revatio in pregnant women, Revatio is not recommended for women 

of childbearing potential unless also using appropriate contraceptive measures. 

 

Pregnancy 

There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct 

or indirect harmful effects with respect to pregnancy and embryonal/foetal development. Studies in 

animals have shown toxicity with respect to postnatal development (see section 5.3).  

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

 

Breast-feeding 

There are no adequate and well controlled studies in lactating women. Data from one lactating woman 

indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk at 
very low levels. No clinical data are available regarding adverse events in breast-fed infants, but 

amounts ingested would not be expected to cause any adverse effects. Prescribers should carefully 

assess the mother’s clinical need for sildenafil and any potential adverse effects on the breast-fed 

child. 

 

Fertility 

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

section 5.3). 

 
4.7 Effects on ability to drive and use machines 

 

Revatio has moderate influence on the ability to drive and use machines. 

 

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware 

of how they might be affected by Revatio, before driving or using machines. 

 

4.8 Undesirable effects 
 

Adverse reactions that resulted from intravenous Revatio use are similar to those associated with oral 

Revatio use. Since there are limited data for intravenous Revatio use and since pharmacokinetic 

models predict that 20 mg oral and 10 mg intravenous formulations will yield similar plasma 

exposures, the safety information for intravenous Revatio is supported by that of oral Revatio. 
 

Intravenous administration 

A 10 mg dose of Revatio solution for injection is predicted to provide total exposure of free sildenafil 

and its N-desmethyl metabolite and their combined pharmacological effects comparable to those of a 

20 mg oral dose. 

 
Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability and 

pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus injection 

to patients with Pulmonary Arterial Hypertension (PAH) who were already receiving and stable on 

oral Revatio 20 mg three times per day. 

 

A total of 10 PAH subjects enrolled and completed the study. The mean postural changes in systolic 

and diastolic blood pressure over time were small (< 10 mmHg) and returned towards baseline beyond 

2 hours. No symptoms of hypotension were associated with these changes. The mean changes in heart 

rate were clinically insignificant. Two subjects experienced a total of 3 adverse reactions (flushing, 

flatulence and hot flush). There was one serious adverse reaction in a subject with severe ischaemic 

cardiomyopathy who experienced ventricular fibrillation and death 6 days post study. It was judged to 

be unrelated to the study medicinal product. 

 



29 

Oral administration 
In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 

207 patients were randomized to and treated with 20 mg, 40 mg or 80 mg TID doses of oral Revatio 

and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall 

frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID 

was 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the 277 subjects treated 

in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day 
(4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 % 

of 183 patients on study treatment were receiving Revatio 80 mg TID.  

 

In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary 

arterial hypertension, a total of 134 patients were treated with oral Revatio (in a fixed titration starting 
from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) and epoprostenol, and 

131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The 

overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events 

was 5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse 

drug reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular 
hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known 

adverse events headache, flushing, pain in extremity and oedema were noted in a higher frequency in 

sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the 

subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg 

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

Revatio 80 mg TID. 
 

In the two-placebo controlled oral Revatio studies adverse events were generally mild to moderate in 

severity. The most commonly reported adverse reactions that occurred (greater or equal to 10 %) on 

Revatio compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity. 

 
Tabulated list of adverse reactions 

Adverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 % 

difference) on Revatio in the pivotal study or in the Revatio combined data set of both the 

placebo-controlled studies in pulmonary arterial hypertension, at oral doses of 20, 40 or 80 mg TID are 

listed in 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. 

 

MedDRA system organ class (V.14.0) Adverse reaction 

Infections and infestations  

Common 

 

cellulitis,influenza, bronchitis,  

sinusitis, rhinitis, gastroenteritis 

Blood and lymphatic system disorders  

Common anaemia 

Metabolism and nutrition disorders  

Common fluid retention 

Psychiatric disorders  

Common insomnia, anxiety 

Nervous system disorders  

Very common headache  

Common migraine, tremor, paraesthesia, burning 

sensation, hypoaesthesia 



30 

Eye disorders  

Common retinal haemorrhage, visual 

impairment, vision blurred, 

photophobia, chromatopsia, cyanopsia, 

eye irritation, ocular hyperaemia  

Uncommon visual acuity reduced, diplopia, 

abnormal sensation in eye  

Not known Non-arteritic anterior ischaemic optic 

neuropathy (NAION)*, Retinal 

vascular occlusion*, Visual field 

defect* 

Ear and labyrinth disorders  

Common vertigo 

Not known sudden hearing loss 

Vascular disorders  

Very common flushing 

Not Known hypotension 

Respiratory, thoracic and mediastinal disorders  

Common epistaxis, cough, nasal congestion  

Gastrointestinal disorders  

Very common diarrhoea, dyspepsia  

Common gastritis, gastrooesophageal reflux 

disease, haemorrhoids, abdominal 

distension, dry mouth 

Skin and subcutaneous tissue disorders  

Common alopecia, erythema, night sweats 

Not known rash 

Musculoskeletal and connective tissue disorders  

Very common pain in extremity 

Common myalgia, back pain  

Renal and urinary disorders  

Uncommon haematuria 

Reproductive system and breast disorders   

Uncommon penile haemorrhage, haematospermia, 

gynaecomastia 

Not known priapism, erection increased 

General disorders and administration site 

conditions 

 

Common pyrexia 

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

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 
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. 

 



31 

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

in the urine. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 
5.1  Pharmacodynamic properties 

 

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). 

 



32 

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, and PAH following surgical 

repair of congenital heart lesions. Patients were randomised to one of four treatment groups: placebo, 

sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients 

randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 

68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline 

6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients 

(63 %) included were diagnosed with primary pulmonary hypertension, 84 (30 %) were diagnosed 

with PAH associated with connective tissue disease and 18 (7 %) of the patients were diagnosed with 

PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional Class 

II (107/277, 39 %) or III (160/277, 58 %) with a mean baseline 6 minute walking distance of 

378 meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4 %) or IV (9/277, 3 %) 

at baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening fraction 

< 0.2 were not studied. 

 

Sildenafil (or placebo) was added to patients’ background therapy which could have included a 

combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of 
prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on 

therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy 

were excluded from the study. 

 

The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance 
(6MWD). A statistically significant increase in 6MWD was observed in all 3 sildenafil dose groups 

compared to those on placebo. Placebo corrected increases in 6MWD were 45 metres (p < 0.0001), 

46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID 

respectively. There was no significant difference in effect between sildenafil doses. For patients with a 

low baseline 6 MWD < 325 m improved efficacy was observed with higher doses (placebo-corrected 
improvements of 58 metres, 65 metres and 87 metres for 20 mg, 40 mg and 80 mg doses TID, 

respectively). 

 

When analysed by WHO functional class, a statistically significant increase in 6MWD was observed 

in the 20 mg dose group. For class II and class III, placebo corrected increases of 49 metres 

(p = 0.0007) and 45 metres (p = 0.0031) were observed respectively. 
 



33 

The improvement in 6MWD was apparent after 4 weeks of treatment and this effect was maintained at 
weeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary and 

connective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAP 

and PVRI. 

 

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial 

pressure (mPAP) and pulmonary vascular resistance (PVR) compared to those on placebo. 
Placebo-corrected treatment effects with mPAP were -2.7 mm Hg (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 %, and 14.4 %). The effect of sildenafil on mortality is unknown. 

 

A greater percentage of patients on each of the sildenafil doses (i.e.  28 %, 36 % and 42 % of subjects 

who received sildenafil 20 mg, 40 mg and 80 mg TID doses, respectively) showed an improvement by 
at least one WHO functional class at week 12 compared to placebo (7 %). The respective odds ratios 

were 2.92 (p=0.0087), 4.32 (p=0.0004) and 5.75 (p<0.0001). 

 

Long-term survival data in naive population 

Patients enrolled into the pivotal oral route study were eligible to enter a long term open label 

extension study. At 3 years 87 % of the patients were receiving a dose of 80 mg TID. A total of 

207 patients were treated with 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 connective tissue disease 

(55/267, 21 %). Most patients were WHO Functional Class II (68/267, 26 %) or III (175/267, 66 %); 

fewer patients were Class I (3/267, 1 %) or IV (16/267, 6 %) at baseline; for a few patients (5/267, 

2 %), the WHO Functional Class was unknown. Patients were randomised to placebo or sildenafil (in 

a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) when 

used in combination with intravenous epoprostenol. 

 

The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance. 
There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk 

distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of 

sildenafil (95 % CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance 

≥ 325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline 

walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients 

with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with PAH 
associated with connective tissue disease. The difference in results between these randomisation 

subgroups may have arisen by chance in view of their limited sample size. 

 

Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial 

Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of 

-3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time to clinical 

worsening was a secondary endpoint as defined as the time from randomisation to the first occurrence 

of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical 

deterioration requiring a change in epoprostenol therapy). Treatment with sildenafil significantly 

delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects 



34 

experienced clinical worsening events in the placebo group (17.6 %) compared with 8 subjects in the 

sildenafil group (6.0 %). 

 

Long-term Survival Data in the background epoprostenol study 

Patients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term open 

label extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg TID. A total of 

134 patients were treated with Revatio in the initial study, and their long term survival status was 

assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year 

survival were 92 %, 81 % and 74 %, respectively. 

 

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

A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjects 

with PAH (WHO FC II and III) who were on bosentan therapy for a minimum of three months. The 

PAH patients included those with Primary PAH, and PAH associated with connective tissue disease. 

Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with 

bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at 

Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from 

baseline on 6MWD observed between sildenafil (20 mg three times a day) and placebo (13.62 m (95% 

CI: -3.89 to 31.12) and 14.08 m (95% CI: -1.78 to 29.95), respectively). 

 

Differences in 6MWD were observed between patients with primary PAH and PAH associated with 

connective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baseline 

were 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52) for the sildenafil and 

placebo groups, respectively. However, for subjects with PAH associated with connective tissue 

disease (36 subjects) mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and 

17.50 m (95% CI: -9.41 to 44.41) for the sildenafil and placebo groups, respectively. 

 

Overall, the adverse events were generally similar between the two treatment groups (sildenafil plus 

bosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used as 

monotherapy (see sections 4.4 and 4.5). 

 

Paediatric population 

 

Persistent pulmonary hypertension of the newborn 

 

A randomized, double-blind, two-arm, parallel-group, placebo-controlled study was conducted in 

59 neonates with persistent pulmonary hypertension of the newborn (PPHN), or hypoxic respiratory 

failure (HRF) and at risk for PPHN with oxygenation index (OI) >15 and <60. The primary objective 

was 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 treatment 

targeting 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. The 

difference 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). For 

patients without treatment failure, the mean time on iNO treatment after initiation of IV study drug 

was 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%) and 

7 (24.1%) subjects in the iNO + IV sildenafil treatment group, respectively, and in 19 (63.3%) and 

2 (6.7%) subjects in the iNO + placebo group, respectively. The most commonly reported 

treatment-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%] 



35 

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). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

The mean absolute oral bioavailability for sildenafil is 41 % (range 25-63 %). In study A1481262 

Cmax, CL and AUC (0-8) of 248 ng/ml, 30.3 l/h and 330 ng h/ml, were observed respectively. The Cmax 
and AUC (0-8) of the N-desmethyl metabolite were 30.8 ng/ml and 147 ng h/ml, respectively. 

 

Distribution 

The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into 

the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration 

of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N-
desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding is 

independent of total drug concentrations. 

 

Biotransformation 

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic 
microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. 

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

for PDE5 approximately 50 % that of the parent drug. The N-desmethyl metabolite is further 

metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial 

hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those of 
sildenafil after 20 mg three times a day oral dosing (translating into a 36 % contribution to sildenafil’s 

pharmacological effects). The subsequent effect on efficacy is unknown. In healthy volunteers, the 

plasma levels of the N-desmethyl metabolite following intravenous dosing are significantly lower than 

those observed following oral dosing. At steady state plasma concentrations of N-desmethyl 

metabolite are approximately 16 % versus 61 % those of sildenafil after IV and oral dosing, 

respectively. 
 

Elimination 

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 Cmax of 100 % and 88 % respectively compared to 
age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax 

values were significantly increased by 200 % and 79 % respectively in subjects with severe renal 

impairment compared to subjects with normal renal function. 

 



36 

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 Cmax (47 %) compared to age-matched 

volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and Cmax 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 Cmin 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. 

 

5.3 Preclinical safety data 

 
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.  

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Glucose 

Water for injections 

 

6.2 Incompatibilities 

 
This medicinal product must not be mixed with other medicinal products or intravenous diluents 

except those mentioned in section 6.6. 

 

6.3 Shelf life 

 
3 years. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 
 

6.5 Nature and contents of container 

 

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

aluminium overseal. 
 



37 

6.6  Special precautions for disposal and other handling  
 

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 9 mg/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. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Upjohn EESV 
Rivium Westlaan 142 

2909 LD Capelle aan den IJssel 

Netherlands 

 

 
8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/05/318/002 

 

 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 28 October 2005 

Date of latest renewal: 23 September 2010 

 

 
10. DATE OF REVISION OF THE TEXT 

 

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

http://www.ema.europa.eu 

 



38 

1.  NAME OF THE MEDICINAL PRODUCT 
 

Revatio 10 mg/ml powder for oral suspension 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 
After reconstitution, each ml of the oral suspension contains 10 mg of sildenafil (as citrate) 

One bottle of reconstituted oral suspension (112 ml) contains 1.12 g of sildenafil (as citrate) 

 

Excipient(s) with known effect 

Each ml of oral suspension contains 250 mg sorbitol. 
 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Powder for oral suspension. 

White to off-white powder. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 
 

Adults 

Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II 

and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension 

and pulmonary hypertension associated with connective tissue disease. 

 

Paediatric population 

Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. 

Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown 

in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart 

disease (see section 5.1). 

 

4.2 Posology and method of administration 
 

Treatment should only be initiated and monitored by a physician experienced in the treatment of 

pulmonary arterial hypertension. In case of clinical deterioration in spite of Revatio treatment, 

alternative therapies should be considered. 

 
Posology 

 

Adults 

The recommended dose is 20 mg three times a day (TID). Physicians should advise patients who 

forget to take Revatio to take a dose as soon as possible and then continue with the normal dose. 
Patients should not take a double dose to compensate for the missed dose. 

 

Paediatric population (1 year to 17 years) 

For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is 10 mg 

(1 ml of reconstituted suspension) three times a day and for patients > 20 kg is 20 mg (2 ml of 

reconstituted suspension) three times a day. Higher than recommended doses should not be used in 

paediatric patients with PAH (see also sections 4.4 and 5.1).  

 



39 

Patients using other medicinal products 
In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A 

downward dose adjustment to 20 mg twice daily should be considered when sildenafil is 

co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A 

downward dose adjustment to 20 mg once daily is recommended in case of co-administration with 

more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone. For the use of 

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

 

Special populations 

 

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

distance could be less in elderly patients. 

  

Renal impairment 

Initial dose adjustments are not required in patients with renal impairment, including severe renal 
impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 20 mg twice daily 

should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated. 

 

Hepatic impairment 

Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and 

B). A downward dose adjustment to 20 mg twice daily should be considered after a careful 
benefit-risk assessment only if therapy is not well-tolerated. 

 

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

section 4.3). 

 

Paediatric population (children less than 1 year and neonates)  

Outside its authorised indications, sildenafil should not be used in neonates with persistent pulmonary 
hypertension of the newborn as risks outweigh the benefits (see section 5.1). The safety and efficacy 

of Revatio in other conditions in children below 1 year of age has not been established. No data are 

available. 

 

Discontinuation of treatment 

Limited data suggest that the abrupt discontinuation of Revatio is not associated with rebound 
worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden 

clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified 

monitoring is recommended during the discontinuation period.  

 

Method of administration 

Revatio powder for oral suspension is for oral use only. The reconstituted oral suspension (a white, 

grape flavoured oral suspension) should be taken approximately 6 to 8 hours apart with or without 

food. 

 

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

 

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

 

4.3 Contraindications 

 

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). 

 



40 

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

4.5). 

 

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

(see section 4.5). 

 

Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic 

neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 

inhibitor exposure (see section 4.4). 

 

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

therefore contraindicated: 

Severe hepatic impairment, 
Recent history of stroke or myocardial infarction, 

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

 

4.4 Special warnings and precautions for use 
 

The efficacy of Revatio has not been established in patients with severe pulmonary arterial 

hypertension (functional class IV). If the clinical situation deteriorates, therapies that are 
recommended at the severe stage of the disease (eg, epoprostenol) should be considered (see section 

4.2). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO 

functional class I pulmonary arterial hypertension. 

 

Studies with sildenafil have been performed in forms of pulmonary arterial hypertension related to 

primary (idiopathic), connective tissue disease associated or congenital heart disease associated forms 
of PAH (see section 5.1). The use of sildenafil in other forms of PAH is not recommended. 

 

In the long term paediatric extension study, an increase in deaths was observed in patients 

administered doses higher than the recommended dose. Therefore, doses higher than the recommended 

doses should not be used in paediatric patients with PAH (see also sections 4.2 and 5.1). 
 

Retinitis pigmentosa 

The safety of sildenafil has not been studied in patients with known hereditary degenerative retinal 

disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal 

phosphodiesterases) and therefore its use is not recommended. 
 

Vasodilatory action 

When prescribing sildenafil, physicians should carefully consider whether patients with certain 

underlying conditions could be adversely affected by sildenafil’s mild to moderate vasodilatory  

effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular 
outflow obstruction or autonomic dysfunction (see section 4.4). 

 

Cardiovascular risk factors 

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular 

events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, 
cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been 

reported in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-

existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual 

intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity. 

It is not possible to determine whether these events are related directly to these factors or to other 
factors. 

 



41 

Priapism 
Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as 

angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may 

predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia). 

 

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In 

the event of an erection that persists longer than 4 hours, the patient should seek immediate medical 
assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency 

could result (see section 4.8). 

 

Vaso-occlusive crises in patients with sickle cell anaemia 

Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell 
anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported 

more commonly by patients receiving Revatio than those receiving placebo leading to the premature 

termination of this study. 

 

Visual events 
Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil 

and other PDE5 inhibitors. Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, 

have been reported spontaneously and in an observational study in connection with the intake 

of sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual defect, the 

treatment should be stopped immediately and alternative treatment should be considered (see section 

4.3). 
 

Alpha-blockers 

Caution is advised when sildenafil is administered to patients taking an alpha-blocker as the 

co-administration may lead to symptomatic hypotension in susceptible individuals (see section 4.5). In 

order to minimise the potential for developing postural hypotension, patients should be 
haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians 

should advise patients what to do in the event of postural hypotensive symptoms.  

 

Bleeding disorders 

Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium 
nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with 

bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these 

patients only after careful benefit-risk assessment. 

 

Vitamin K antagonists 

In pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding 
when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients 

with pulmonary arterial hypertension secondary to connective tissue disease. 

 

Veno-occlusive disease 

No data are available with sildenafil in patients with pulmonary hypertension associated with 
pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been 

reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should 

signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary 

hypertension, the possibility of associated veno-occlusive disease should be considered. 

 

Fructose intolerance 

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

 

Use of sildenafil with bosentan 
The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively 

demonstrated (see sections 4.5 and 5.1). 

 



42 

Concomitant use with other PDE5 inhibitors 
The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, 

including Viagra, has not been studied in PAH patients and such concomitant use is not recommended 

(see section 4.5). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Effects of other medicinal products on sildenafil 

 

In vitro studies 

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major 
route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil 

clearance and inducers of these isoenzymes may increase sildenafil clearance. For dose 

recommendations, see sections 4.2 and 4.3. 

 

In vivo studies  

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

and 5.1). 

 

The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial 

hypertension (eg, ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, 

caution is recommended in case of co-administration. 

 

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been 

studied in pulmonary arterial hypertension patients (see section 4.4). 

 

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a 

reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with 

CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the 
only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with 

pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and 

CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients 

not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg 

three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration 

range covers the increase in sildenafil exposure observed in specifically designed drug interaction 
studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, 

ketoconazole, itraconazole, ritonavir). 

 

CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in 

pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with 
CYP3A4 inducer bosentan. 

 

Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 

125 mg twice daily with sildenafil 80 mg three times a day (at steady state) concomitantly 

administered during 6 days in healthy volunteers resulted in a 63 % decrease of sildenafil AUC. A 
population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials 

including a 12 week study to assess the efficacy and safety of oral sildenafil 20 mg three times a day 

when added to a stable dose of bosentan (62.5 mg – 125 mg twice a day) indicated a decrease in 

sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see 

sections 4.4 and 5.1). 

 
Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 

inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine. 

 

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at 

steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300 % (4-fold) 
increase in sildenafil Cmax and a 1,000 % (11-fold) increase in sildenafil plasma AUC. At 24 hours, the 



43 

plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml 
when sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broad 

range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with 

ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3). 

 

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state 

(1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140 % increase in 
sildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir 

pharmacokinetics. For dose recommendations, see section 4.2. 

 

When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 

inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in sildenafil 
systemic exposure (AUC). For dose recommendations, see section 4.2. In healthy male volunteers, 

there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, 

elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite. 

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

CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil concentrations when co-administered 
with sildenafil (50 mg) to healthy volunteers. No dose adjustment is required. 

 

The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected 

to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, 

telithromycin and nefazodone are expected to have an effect in between that of ritonavir and CYP3A4 

inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. Therefore 
dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2). 

 

The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that 

co-administration of beta-blockers in combination with CYP3A4 substrates might result in an 

additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone. 
 

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest 

increases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use of 

sildenafil and grapefruit juice is not recommended.  

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

of sildenafil. 

 

Co-administration of oral contraceptives (ethinyloestradiol 30 g and levonorgestrel 150 g) did not 

affect the pharmacokinetics of sildenafil. 

 
Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has 

the potential to have serious interaction with sildenafil (see section 4.3). 

 

Effects of sildenafil on other medicinal products 

 

In vitro studies 

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 

(IC50 > 150 M). 

 

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

 

In vivo studies 

No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide 

(250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9. 
 

Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that 

sildenafil does not have a clinically relevant effect on CYP3A4. 



44 

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

 

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

(150 mg). 

 

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

 

In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50 % 

increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from a 

study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) indicated 
an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with co-administration of steady-state 

sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-

administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1). 

 

In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in 
hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. 

The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These 

additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was 

administered alone to healthy volunteers. 

 

In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and 
sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign 

prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean 

additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 

8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg, 

11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were 
administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports 

of patients who experienced symptomatic postural hypotension. These reports included dizziness and 

lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking 

alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 

4.4). 

 

Sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease 

inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor. 
 

Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was 

shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide 

donors or nitrates in any form is therefore contraindicated (see section 4.3).  

 
Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 

inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the 

hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the 

combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including 

sildenafil, is contraindicated (see section 4.3). 
 

Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives 

(ethinyloestradiol 30 g and levonorgestrel 150 g). 

 

Paediatric population 

Interaction studies have only been performed in adults. 

 



45 

4.6 Fertility, pregnancy and lactation 
 

Women of childbearing potential and contraception in males and females 

Due to lack of data on effects of Revatio in pregnant women, Revatio is not recommended for women 

of childbearing potential unless also using appropriate contraceptive measures. 

 

Pregnancy 

There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct 
or indirect harmful effects with respect to pregnancy and embryonal/foetal development. Studies in 

animals have shown toxicity with respect to postnatal development (see section 5.3).  

 

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

 

Breast-feeding 
There are no adequate and well controlled studies in lactating women. Data from one lactating woman 

indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk at 

very low levels. No clinical data are available regarding adverse events in breast-fed infants, but 

amounts ingested would not be expected to cause any adverse effects. Prescribers should carefully 

assess the mother’s clinical need for sildenafil and any potential adverse effects on the breast-fed 
child. 

 

Fertility 

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

section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

Revatio has moderate influence on the ability to drive and use machines. 

 

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware 

of how they might be affected by Revatio, before driving or using machines.  
 

4.8 Undesirable effects 

 

Summary of the safety profile 

In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 
207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg TID doses of Revatio and 

70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall 

frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID 

was 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the 277 subjects treated 

in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day 
(4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 % 

of 183 patients on study treatment were receiving Revatio 80 mg TID. 

 

In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary 

arterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting from 

20 mg, to 40 mg and then 80 mg, three times a day as tolerated) and epoprostenol, and 131 patients 
were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall 

frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 

5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse 

reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular 

hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known 
adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency 

in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the 

subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg 

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

Revatio 80 mg TID. 



46 

 
In the two-placebo controlled studies adverse events were generally mild to moderate in severity. The 

most commonly reported adverse reactions that occurred (greater or equal to 10 %) on Revatio 

compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity. 

 

Tabulated list of adverse reactions 

Adverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 % 

difference) on Revatio in the pivotal study or in the Revatio combined data set of both the 

placebo-controlled studies in pulmonary arterial hypertension,, at doses of 20, 40 or 80 mg TID are 

listed in the table below by class and frequency grouping (very common ( 1/10), common ( 1/100 to 

< 1/10), uncommon ( 1/1000 to < 1/100) and not known (cannot be estimated from the available 

data). Within each frequency grouping, adverse reactions are presented in order of decreasing 

seriousness. 

 

Reports from post-marketing experience are included in italics. 

 

MedDRA system organ class (V.14.0) Adverse reaction 

Infections and infestations  

Common 

 

cellulitis, influenza, bronchitis, 

sinusitis, rhinitis, gastroenteritis 

Blood and lymphatic system disorders  

Common anaemia  

Metabolism and nutrition disorders  

Common fluid retention 

Psychiatric disorders  

Common insomnia, anxiety 

Nervous system disorders  

Very common headache  

Common migraine, tremor, paraesthesia, burning 

sensation, hypoaesthesia 

Eye disorders  

Common retinal haemorrhage, visual 

impairment, vision blurred, 

photophobia, chromatopsia, cyanopsia, 

eye irritation, ocular hyperaemia   

Uncommon visual acuity reduced, diplopia, 

abnormal sensation in eye  

Not known Non-arteritic anterior ischaemic optic 

neuropathy (NAION)*, Retinal 

vascular occlusion*, Visual field 

defect* 

Ear and labyrinth disorders  

Common vertigo 

Not known sudden hearing loss 

Vascular disorders  

Very common flushing 

Not known hypotension 

Respiratory, thoracic and mediastinal disorders  

Common epistaxis, cough, nasal congestion  



47 

Gastrointestinal disorders  

Very common diarrhoea, dyspepsia  

Common gastritis, gastrooesophageal reflux 

disease, haemorrhoids, abdominal 

distension, dry mouth 

Skin and subcutaneous tissue disorders  

Common alopecia, erythema, night sweats 

Not known rash 

Musculoskeletal and connective tissue disorders  

Very common pain in extremity 

Common myalgia, back pain  

Renal and urinary disorders  

Uncommon haematuria 

Reproductive system and breast disorders   

Uncommon penile haemorrhage, haematospermia, 

gynaecomastia 

Not known priapism, erection increased 

General disorders and administration site 

conditions 

 

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

Paediatric population 

In the placebo-controlled study of Revatio in patients 1 to 17 years of age with pulmonary arterial 

hypertension, a total of 174 patients were treated three times a day with either low (10 mg in patients 

> 20 kg; no patients ≤ 20 kg received the low dose), medium (10 mg in patients ≥ 8-20 kg; 20 mg in 

patients ≥ 20-45 kg; 40 mg in patients > 45 kg) or high dose (20 mg in patients ≥ 8-20 kg; 40 mg in 

patients ≥ 20-45 kg; 80 mg in patients > 45 kg) regimens of Revatio and 60 were treated with placebo.   

 

The adverse reactions profile seen in this paediatric study was generally consistent with that in adults 

(see table above). The most common adverse reactions that occurred (with a frequency ≥ 1 %) in 
Revatio patients (combined doses) and with a frequency > 1 % over placebo patients were pyrexia, 

upper respiratory tract infection (each 11.5%), vomiting (10.9%), erection increased (including 

spontaneous penile erections in male subjects) (9.0%), nausea, bronchitis (each 4.6%), pharyngitis 

(4.0%), rhinorrhoea (3.4%), and pneumonia, rhinitis (each 2.9%). 

 
Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered 

the long-term extension study. Subjects on active sildenafil therapy continued on the same treatment 

regimen, while those in the placebo group in the short-term study were randomly reassigned to 

sildenafil treatment. 

 

The most common adverse reactions reported across the duration of the short-term and long-term 
studies were generally similar to those observed in the short-term study. Adverse reactions reported in 

>10% of 229 subjects treated with sildenafil (combined dose group, including 9 patients that did not 

continue into the long-term study) were upper respiratory infection (31%), headache (26%), vomiting 

(22%), bronchitis (20%), pharyngitis (18%), pyrexia (17%), diarrhoea (15%), and influenza, epistaxis 

(12% each). Most of these adverse reactions were considered mild to moderate in severity. 
 

Serious adverse events were reported in 94 (41%) of the 229 subjects receiving sildenafil. Of the 94 

subjects reporting a serious adverse event, 14/55 (25.5%) subjects were in the low dose group, 35/74 

(47.3%) in the medium dose group, and 45/100 (45%) in the high dose group. The most common 

serious adverse events that occurred with a frequency ≥ 1 % in sildenafil patients (combined doses) 
were pneumonia (7.4%), cardiac failure, pulmonary hypertension (each 5.2%), upper respiratory tract 

infection (3.1%), right ventricular failure, gastroenteritis (each 2.6%), syncope, bronchitis, 

bronchopneumonia, pulmonary arterial hypertension (each 2.2%), chest pain, dental caries (each 

1.7%), and cardiogenic shock, gastroenteritis viral, urinary tract infection (each 1.3%). 

 



48 

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

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at 

lower doses, but the incidence rates and severities were increased. At single doses of 200 mg the 
incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, and altered 

vision) was increased. 

 

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is 

not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated 
in the urine. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 
 

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

 

Mechanism of action 

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific 
phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart from 

the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the 

pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth 

muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to 

vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic 
circulation. 

 

Pharmacodynamic effects 

Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 

than on other known phosphodiesterases. There is a10-fold selectivity over PDE6 which is involved in 

the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over 
700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold 

selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control 

of cardiac contractility. 

 

Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of 
cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients 

with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was 

a decrease of 9.4 mm Hg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a 

day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were 

observed (a reduction in both systolic and diastolic pressure of 2 mm Hg). At the recommended dose 
of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. 

 

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant 

effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial 

hypertension no clinically relevant effects on the ECG were reported. 
In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with 

severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean 



49 

resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to 
baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on 

cardiac output, and did not impair blood flow through the stenosed coronary arteries.  

 

Mild and transient differences in colour discrimination (blue/green) were detected in some subjects 

using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident 

after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related 
to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has 

no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients 

with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) 

demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour 

discrimination simulated traffic light, Humphrey perimeter and photostress). 
 

Clinical efficacy and safety 

 

Efficacy in adult patients with pulmonary arterial hypertension (PAH) 

A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary 

pulmonary hypertension, PAH associated with connective tissue disease, and PAH following surgical 

repair of congenital heart lesions. Patients were randomised to one of four treatment groups: placebo, 

sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients 

randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 68 

(25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline 

6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients 

(63 %) included were diagnosed with primary pulmonary hypertension, 84 (30 %) were diagnosed 

with PAH associated with connective tissue disease and 18 (7 %) of the patients were diagnosed with 

PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional Class 

II (107/277, 39 %) or III (160/277, 58 %) with a mean baseline 6 minute walking distance of 

378 meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4 %) or IV (9/277, 3 %) 

at baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening fraction 

< 0.2 were not studied. 

 

Sildenafil (or placebo) was added to patients’ background therapy which could have included a 

combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of 

prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on 
therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy 

were excluded from the study. 

 

The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance 

(6MWD). A statistically significant increase in 6MWD was observed in all 3 sildenafil dose groups 
compared to those on placebo. Placebo corrected increases in 6MWD were 45 metres (p < 0.0001), 

46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID, 

respectively. There was no significant difference in effect between sildenafil doses.  For patients with a 

baseline 6MWD < 325 m improved efficacy was observed with higher doses (placebo-corrected 

improvements of 58 metres, 65 metres and 87 metres for 20 mg, 40 mg and 80 mg doses TID, 

respectively). 
 

When analysed by WHO functional class, a statistically significant increase in 6MWD was observed 

in the 20 mg dose group. For class II and class III, placebo corrected increases of 49 metres 

(p = 0.0007) and 45 metres (p = 0.0031) were observed respectively. 

 
The improvement in 6MWD was apparent after 4 weeks of treatment and this effect was maintained at 

weeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary and 

connective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAP 

and PVRI. 

 
Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial 

pressure (mPAP) and pulmonary vascular resistance (PVR) compared to those on placebo. Placebo-



50 

corrected treatment effects with mPAP were -2.7 mmHg (p = 0.04), -3.0 mm Hg (p = 0.01) and 
-5.1 mm Hg (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID respectively. Placebo-corrected 

treatment effects with PVR were -178 dyne.sec/cm5 (p=0.0051), -195 dyne.sec/cm5 (p=0.0017) and 

-320 dyne.sec/cm5 (p<0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID, respectively.The percent 

reduction at 12 weeks for sildenafil 20 mg, 40 mg and 80 mg TID in PVR (11.2 %, 12.9 %, 23.3 %) 

was proportionally greater than the reduction in systemic vascular resistance (SVR) (7.2 %, 5.9 %, 

14.4 %). The effect of sildenafil on mortality is unknown. 
 

A greater percentage of patients on each of the sildenafil doses (i.e. 28 %, 36 % and 42 % of subjects 

who received sildenafil 20 mg, 40 mg and 80 mg TID doses, respectively) showed an improvement by 

at least one WHO functional class at week 12 compared to placebo (7 %). The respective odds ratios 

were 2.92 (p=0.0087), 4.32 (p=0.0004) and 5.75 (p<0.0001). 

 

Long-term survival data in naive population 

Patients enrolled into the pivotal study were eligible to enter a long term open label extension study. 

At 3 years 87 % of the patients were receiving a dose of 80 mg TID. A total of 207 patients were 

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

A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who 

were stabilised on intravenous epoprostenol. The PAH patients included those with Primary 

Pulmonary Arterial Hypertension (212/267, 79 %) and PAH associated with connective tissue disease 

(55/267, 21 %). Most patients were WHO Functional Class II (68/267, 26 %) or III (175/267, 66 %); 

fewer patients were Class I (3/267, 1 %) or IV (16/267, 6 %) at baseline; for a few patients (5/267, 

2 %), the WHO Functional Class was unknown. Patients were randomised to placebo or sildenafil (in 

a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) when 

used in combination with intravenous epoprostenol. 

 

The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance. 

There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk 
distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of 

sildenafil (95 % CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance 

≥ 325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline 

walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients 

with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with PAH 
associated with connective tissue disease. The difference in results between these randomisation 

subgroups may have arisen by chance in view of their limited sample size. 

 

Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial 

Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of 

-3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time to clinical 

worsening was a secondary endpoint as defined as the time from randomisation to the first occurrence 

of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical 

deterioration requiring a change in epoprostenol therapy). Treatment with sildenafil significantly 

delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects 

experienced clinical worsening events in the placebo group (17.6 %) compared with 8 subjects in the 

sildenafil group (6.0 %). 

 

Long-term Survival Data in the background epoprostenol study 

Patients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term open 

label extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg TID. A total of 

134 patients were treated with Revatio in the initial study, and their long term survival status was 



51 

assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year 

survival were 92 %, 81 % and 74 %, respectively. 

 

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

A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjects 

with PAH (WHO FC II and III) who were on bosentan therapy for a minimum of three months. The 

PAH patients included those with Primary PAH, and PAH associated with connective tissue disease. 

Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with 

bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at 

Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from 

baseline on 6MWD observed between sildenafil (20 mg three times a day) and placebo (13.62 m (95% 

CI: -3.89 to 31.12) and 14.08 m (95% CI: -1.78 to 29.95), respectively). 

 

Differences in 6MWD were observed between patients with primary PAH and PAH associated with 

connective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baseline 

were 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52) for the sildenafil and 

placebo groups, respectively. However, for subjects with PAH associated with connective tissue 

disease (36 subjects) mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and 

17.50 m (95% CI: -9.41 to 44.41) for the sildenafil and placebo groups, respectively. 

 

Overall, the adverse events were generally similar between the two treatment groups (sildenafil plus 

bosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used as 

monotherapy (see sections 4.4 and 4.5). 

 

Paediatric population 

 

Pulmonary arterial hypertension 

 

A total of 234 subjects aged 1 to 17 years were treated in a randomized, double-blind, multi-centre, 

placebo controlled parallel group, dose ranging study. Subjects (38 % male and 62 % female) had a 

body weight  8 kg, and had primary pulmonary hypertension (PPH) [33 %], or PAH secondary to 

congenital heart disease [systemic-to-pulmonary shunt 37 %, surgical repair 30 %]. In this trial, 63 of 

234 (27 %) patients were < 7 years old (sildenafil low dose = 2; medium dose = 17; high dose = 28; 

placebo = 16) and 171 of 234 (73 %) patients were 7 years or older (sildenafil low dose = 40; medium 

dose = 38; and high dose = 49; placebo = 44). Most subjects were WHO Functional Class I (75/234, 

32 %) or II (120/234, 51 %) at baseline; fewer patients were Class III (35/234, 15 %) or IV (1/234, 

0.4 %); for a few patients (3/234, 1.3 %), the WHO Functional Class was unknown. 

 

Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and 

endothelin receptor antagonists was not permitted in the study, and neither was arginine 

supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors. 

 

The primary objective of the study was to assess the efficacy of 16 weeks of chronic treatment with 

oral sildenafil in paediatric subjects to improve exercise capacity as measured by the Cardiopulmonary 

Exercise Test (CPET) in subjects who were developmentally able to perform the test, n = 115). 

Secondary endpoints included haemodynamic monitoring, symptom assessment, WHO functional 

class, change in background treatment, and quality of life measurements. 

 

Subjects were allocated to one of three sildenafil treatment groups, low (10 mg), medium (10-40 mg) 

or high dose (20-80 mg) regimens of Revatio given three times a day, or placebo. Actual doses 

administered within a group were dependent on body weight (see Section 4.8). The proportion of 

subjects receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel 

blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (47.7 %) and 

the placebo treatment group (41.7 %). 

 



52 

The primary endpoint was the placebo-corrected percentage change in peak VO2 from baseline to 

week 16 assessed by CPET in the combined dose groups (Table 2). A total of 106 out of 234 (45 %) 

subjects were evaluable for CPET, which comprised those children ≥ 7 years old and developmentally 

able to perform the test. Children < 7 years (sildenafil combined dose = 47; placebo = 16) were 

evaluable only for the secondary endpoints. Mean baseline peak volume of oxygen consumed (VO2) 

values were comparable across the sildenafil treatment groups (17.37 to 18.03 ml/kg/min), and slightly 

higher for the placebo treatment group (20.02 ml/kg/min). The results of the main analysis (combined 

dose groups versus placebo) were not statistically significant (p = 0.056) (see Table 2). The estimated 

difference between the medium sildenafil dose and placebo was 11.33 % (95 % CI: 1.72 to 20.94) (see 

Table 2). 

 

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

 

Treatment group Estimated difference 95 % Confidence interval 

Low dose 

(n=24) 

3.81 

 

-6.11, 13.73 

Medium dose 

(n=26) 

11.33 

 

1.72, 20.94 

High dose 

(n=27) 

7.98 

 

-1.64, 17.60 

Combined dose groups 
(n=77) 

7.71 
(p = 0.056) 

-0.19, 15.60 

n=29 for placebo group 

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

weight group 

 

Dose related improvements were observed with pulmonary vascular resistance index (PVRI) and mean 

pulmonary arterial pressure (mPAP). The sildenafil medium and high dose groups both showed PVRI 

reductions compared to placebo, of 18 % (95 %CI: 2 % to 32 %) and 27 % (95 %CI: 14 % to 39 %), 

respectively; whilst the low dose group showed no significant difference from placebo (difference of 

2 %). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared 

to placebo, of -3.5 mmHg (95 %CI: -8.9, 1.9) and -7.3 mmHg (95 %CI: -12.4, -2.1), respectively; 

whilst the low dose group showed little difference from placebo (difference of 1.6 mmHg). 

Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10 %, 

4 % and 15 % for the low, medium and high dose groups respectively. 

 

Significant improvements in functional class were demonstrated only in subjects on sildenafil high 

dose compared to placebo. Odds ratios for the sildenafil low, medium and high dose groups compared 

to placebo were 0.6 (95 % CI: 0.18, 2.01), 2.25 (95 % CI: 0.75, 6.69) and 4.52 (95 % CI: 1.56, 13.10), 

respectively. 

 

Long term extension data 

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered 

the long-term extension study. Subjects who had been in the placebo group in the short-term study 

were randomly reassigned to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium or 

high dose groups (1:1), while subjects weighing > 20 kg entered the low, medium or high dose groups 

(1:1:1). Of the total 229 subjects who received sildenafil, there were 55, 74, and 100 subjects in the 

low, medium and high dose groups, respectively. Across the short-term and long-term studies, the 

overall duration of treatment from start of double-blind for individual subjects ranged from 3 to 3129 

days. By sildenafil treatment group, median duration of sildenafil treatment was 1696 days (excluding 

the 5 subjects who received placebo in double-blind and were not treated in the long-term extension 

study). 

 
Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94 %, 

93 % and 85 % in the low, medium and high dose groups, respectively; for patients ≤ 20 kg in weight 



53 

at baseline, the survival estimates were 94 % and 93 % for subjects in the medium and high dose 
groups 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 or 

reported as part of the survival follow-up. 37 deaths occurred prior to a decision taken by the Data 

Monitoring Committee to down titrate subjects to a lower dosage, based on an observed mortality 
imbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was 

5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, 

respectively. An additional 5 deaths were reported subsequently. The causes of deaths were related to 

PAH. Higher than recommended doses should not be used in paediatric patients with PAH (see 

sections 4.2 and 4.4). 

 

Peak VO2 was assessed 1 year after the start of the placebo-controlled study. Of those sildenafil treated 

subjects developmentally able to perform the CPET 59/114 subjects (52 %) had not shown any 

deterioration in Peak VO2 from start of sildenafil. Similarly 191 of 229 subjects (83 %) who had 

received sildenafil had either maintained or improved their WHO Functional Class at 1 year 

assessment. 

 

Persistent pulmonary hypertension of the newborn 

 

A randomized, double-blind, two-arm, parallel-group, placebo-controlled study was conducted in 

59 neonates with persistent pulmonary hypertension of the newborn (PPHN), or hypoxic respiratory 

failure (HRF) and at risk for PPHN with oxygenation index (OI) >15 and <60. The primary objective 

was 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 treatment 

targeting 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. The 

difference 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). For 

patients without treatment failure, the mean time on iNO treatment after initiation of IV study drug 

was 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%) and 

7 (24.1%) subjects in the iNO + IV sildenafil treatment group, respectively, and in 19 (63.3%) and 

2 (6.7%) subjects in the iNO + placebo group, respectively. The most commonly reported 

treatment-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). 

 

5.2 Pharmacokinetic properties 
 

Absorption 

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 

120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral 

bioavailability is 41 % (range 25-63 %). After oral three times a day dosing of sildenafil, AUC and 
Cmax increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg three 

times a day a more than dose proportional increase in sildenafil plasma levels has been observed. In 

pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg three times a 

day was on average 43 % (90 % CI: 27 % -60 %) higher compared to the lower doses.  

 



54 

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in Tmax of 
60 minutes and a mean reduction in Cmax of 29 % however, the extent of absorption was not 

significantly affected (AUC decreased by 11 %). 

 

Distribution 

The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into 

the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration 
of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N-

desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding is 

independent of total drug concentrations. 

 

Biotransformation 
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic 

microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. 

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

for PDE5 approximately 50 % that of the parent drug. The N-desmethyl metabolite is further 

metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial 
hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those of 

sildenafil after 20 mg three times a day dosing (translating into a 36 % contribution to sildenafil’s 

pharmacological effects). The subsequent effect on efficacy is unknown. 

 

Elimination 

The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3-5 h. After 
either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the 

faeces (approximately 80 % of administered oral dose) and to a lesser extent in the urine 

(approximately 13 % of administered oral dose). 

 

Pharmacokinetics in special patient groups 

 

Elderly 

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in 

approximately 90 % higher plasma concentrations of sildenafil and the active N-desmethyl metabolite 

compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma 
protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 

40 %. 

 

Renal insufficiency 

In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml/min), the 
pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. In volunteers 

with severe renal impairment (creatinine clearance < 30 ml/min), sildenafil clearance was reduced, 

resulting in mean increases in AUC and Cmax of 100 % and 88 % respectively compared to 

age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax 

values were significantly increased by 200 % and 79 % respectively in subjects with severe renal 
impairment compared to subjects with normal renal function. 

 

Hepatic insufficiency 

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) sildenafil clearance 

was reduced, resulting in increases in AUC (85 %) and Cmax (47 %) compared to age-matched 
volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and Cmax values 

were significantly increased by 154 % and 87 %, respectively in cirrhotic subjects compared to 

subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely 

impaired hepatic function have not been studied. 

 

Population pharmacokinetics 
In patients with pulmonary arterial hypertension, the average steady state concentrations were 20-50 % 

higher over the investigated dose range of 20–80 mg three times a day compared to healthy volunteers. 

There was a doubling of the Cmin compared to healthy volunteers. Both findings suggest a lower 



55 

clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterial 
hypertension compared to healthy volunteers. 

 

Paediatric population 

From the analysis of the pharmacokinetic profile of sildenafil in patients involved in the paediatric 

clinical trials, body weight was shown to be a good predictor of drug exposure in children. Sildenafil 

plasma concentration half-life values were estimated to range from 4.2 to 4.4 hours for a range of 10 to 

70 kg of body weight and did not show any differences that would appear as clinically relevant. Cmax 

after a single 20 mg sildenafil dose administered PO was estimated at 49, 104 and 165 ng/ml for 70, 
20 and 10 kg patients, respectively. Cmax after a single 10 mg sildenafil dose administered PO was 

estimated at 24, 53 and 85 ng/ml for 70, 20 and 10 kg patients, respectively. Tmax was estimated at 

approximately 1 hour and was almost independent from body weight. 

 

5.3 Preclinical safety data 
 

Non-clinical data revealed no special hazard for humans based on conventional studies of safety 

pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, toxicity to 

reproduction and development. 

 

In pups of rats which were pre- and postnatally treated with 60 mg/kg sildenafil, a decreased litter size, 
a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were 

approximately fifty times the expected human exposure at 20 mg three times a day. Effects in 

non-clinical studies were observed at exposures considered sufficiently in excess of the maximum 

human exposure indicating little relevance to clinical use. 

 

There were no adverse reactions, with possible relevance to clinical use, seen in animals at clinically 

relevant exposure levels which were not also observed in clinical studies. 

 

 

6. PHARMACEUTICAL PARTICULARS 
 

6.1 List of excipients 
 

Powder for oral suspension: 

Sorbitol 
Citric acid anhydrous 

Sucralose  

Sodium citrate 

Xanthan gum 

Titanium dioxide (E171) 
Sodium benzoate (E211) 

Silica, colloidal anhydrous 

 

Grape flavour: 

Maltodextrin 

Grape juice concentrate 
Gum acacia 

Pineapple juice concentrate 

Citric acid anhydrous 
Natural flavouring 

 
6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life  
 



56 

2 years. 
 

After reconstitution, the oral suspension is stable for 30 days. 

 

6.4 Special precautions for storage 

 

Powder 
Do not store above 30°C. 

Store in the original package in order to protect from moisture. 

 

Oral suspension 

Store below 30°C or in refrigerator (2°C to 8°C). Do not freeze. 
 

For storage conditions after reconstitution of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container 

 
One 125 ml amber glass bottle (with a polypropylene screw cap) contains 32.27 g of powder for oral 

suspension. 

 

Once reconstituted the bottle contains 112 ml of oral suspension, of which 90 ml is intended for dosing 

and administration. 

 

Pack size: 1 bottle 

 

Each pack also contains a polypropylene measuring cup (graduated to indicate 30 ml), polypropylene 

oral dosing syringe (3 ml) with HDPE plunger and a LDPE press-in bottle adaptor. 

 
6.6 Special precautions for disposal and other handling 

 

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

requirements. 

 

It is recommended that a pharmacist reconstitutes Revatio oral suspension prior to its dispensing to the 

patient.  

 
Reconstitution instructions 

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

to reconstitute the contents of the bottle 

 

1. Tap the bottle to release the powder. 
2. Remove the cap. 
3. Measure 30 ml of water by filling the measuring cup (included in the carton) to the marked 

line then pour the water into the bottle. Using the cup measure another 30 ml of water and add 

this to the bottle (figure 1). 

 



57 

 
figure 1 

 
 

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

 
figure 2 
 

 

5. Remove the cap. 
6. Using the cup measure another 30 ml of water and add this to the bottle. You should always 

add a total of 90 ml (3 x 30 ml) of water irrespective of the dose you are taking (figure 3).  

 
figure 3 

 
 

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



58 

 
figure 4 

 
 

8. Remove the cap. 
9. Press the bottle adaptor into the neck of the bottle (as shown on figure 5 below). The adaptor 

is provided so that you can fill the oral dosing syringe with medicine from the bottle. Replace 

the cap on the bottle.  

 
figure 5 

 
 

10. When reconstituted the powder provides a white grape flavoured oral suspension. Write the 
date of expiry of the reconstituted oral suspension on the bottle label (the date of expiry of the 

reconstituted oral suspension is 30 days from the date of reconstitution). Any unused oral 

suspension should be discarded or returned to your pharmacist after this date. 

 

 
Instructions for use 

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



59 

 
figure 6 

 
 

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

 
figure 7 

 
 

3. Turn the bottle upside down while holding the oral dosing syringe in place. Slowly pull back 
the plunger of the oral dosing syringe to the graduation mark that marks the dose for you 

(withdrawing 1 ml provides a 10 mg dose, withdrawing 2 ml provides a 20 mg dose). To 

measure the dose accurately, the top edge of the plunger should be lined up with the 

appropriate graduated mark on the oral dosing syringe (figure 8). 



60 

 
figure 8 

 
 

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

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

6. Put the tip of the oral dosing syringe into the mouth. Point the tip of the oral dosing syringe 
towards the inside of the cheek. SLOWLY push down the plunger of the oral dosing syringe. 
Do not squirt the medicine out quickly. If the medicine is to be given to a child, make sure the 

child is sitting, or is held, upright before giving the medicine (figure 9). 

 
figure 9 

 
 

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

Cleaning and storing the syringe: 

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

parts in water. 

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

medicine. 
 

Once reconstituted, the oral suspension should only be administered using the oral dosing syringe 

supplied with each pack. Refer to the patient leaflet for more detailed instructions for use. 

 

 



61 

7. MARKETING AUTHORISATION HOLDER 
 

Upjohn EESV 

Rivium Westlaan 142 

2909 LD Capelle aan den IJssel 

Netherlands 

 
 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/05/318/003 

 
 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 28 October 2005 

Date of latest renewal: 23 September 2010 
 

 

10. DATE OF REVISION OF THE TEXT 

 

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

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



62 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 



63 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

 

Name and address of the manufacturer(s) responsible for batch release 

 

Fareva Amboise 

Zone Industrielle 

29 route des Industries 

37530 Pocé-sur-Cisse 

France 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic Safety Update Reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal.  

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicine Agency; 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result  

of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures  

 

The Marketing Authorisation Holder (MAH) shall agree the details of a controlled distribution system 

for the 20 ml vial of Revatio 0.8 mg/ml solution for injection with the National Competent Authorities 

and must implement such programme nationally to ensure that prior to prescribing all healthcare 

professionals who intend to prescribe and/or dispense Revatio 0.8 mg/ml solution for injection are 

provided with the following: 

- Information for healthcare professionals 
- Copy of the Summary of Product Characteristics (SPC) 
- Data Capture Form (DCF) designed to facilitate reporting of events of hypotension and 

associated problems 

The Information for healthcare professionals should contain the following key elements: 

- Information about the Pharmacovigilance Monitoring Programme regarding the potential risk 
of clinically relevant hypotension and related problems to be put into place with the use of the 

DCF. 



64 

 

The Marketing Authorisation Holder shall agree the Information for healthcare professionals, and the 

healthcare professionals to be targeted, with the national competent authority of each Member State 

prior to the launch of the 20 ml vial of Revatio 0.8 mg/ml solution for injection in that country. 

 



65 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 



66 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING



67 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER PACKAGING/CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Revatio 20 mg film-coated tablets 

Sildenafil  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose monohydrate. 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

90 film-coated tablets 

90 x 1 film-coated tablets 

300 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



68 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Upjohn EESV 
Rivium Westlaan 142 

2909 LD Capelle aan den IJssel 

Netherlands 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/318/001 

EU/1/05/318/004 

EU/1/05/318/005 

 

 

13. BATCH NUMBER 

 

Batch 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE  

 

Revatio 20 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN:  



69 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 

OUTER CARTON  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Revatio 0.8 mg/ml solution for injection 

Sildenafil 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

sildenafil, as citrate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains glucose and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

1 vial 10 mg/12.5 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Intravenous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 



70 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Upjohn EESV 

Rivium Westlaan 142 

2909 LD Capelle aan den IJssel 

Netherlands 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/318/002 

 

 

13. BATCH NUMBER 

 

Batch  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE  

 

Revatio 0.8 mg/ml 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 
 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN:  

 



71 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  

 

VIAL LABEL  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Revatio 0.8 mg/ml solution for injection 

Sildenafil 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

sildenafil, as citrate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains glucose and water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

1 vial 10 mg/12.5 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Intravenous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

 



72 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Upjohn EESV 

Rivium Westlaan 142 

2909 LD Capelle aan den IJssel 

Netherlands 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/318/002 

 

 

13.  BATCH NUMBER 

 

Batch  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE  

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

 

 



73 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS 

  

IMMEDIATE PACKAGING/BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Revatio 20 mg tablets 

Sildenafil  

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Upjohn 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

LOT 

 

 

5. OTHER 

 

 



74 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Revatio 10 mg/ml powder for oral suspension 

Sildenafil  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Once reconstituted one bottle contains 1.12 g of sildenafil (as citrate) with a final volume of 112 ml. 

Each ml of the reconstituted suspension contains 10 mg of sildenafil (as citrate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains sorbitol. 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for oral suspension 

1 bottle  

1 press-in bottle adapter, 1 measuring cup and 1 oral dosing syringe 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Shake bottle well before use. 

Read the package leaflet before use. 

Oral use. 

 

Reconstitution instructions: 

Tap the bottle to release the powder and remove the cap. 

Add a total of 90 ml of water (3 x 30 ml) strictly following the package leaflet, ensuring the bottle is 

shaken vigorously after adding 60 ml and the remaining 30 ml. Remove the cap again, press the bottle 

adaptor into the neck of the bottle. Note: Expires 30 days after reconstitution. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 



75 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

After reconstitution: Store below 30°C or in refrigerator at 2°C to 8°C. Do not freeze. Discard any 

remaining oral suspension 30 days after reconstitution. 

 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Upjohn EESV 

Rivium Westlaan 142 
2909 LD Capelle aan den IJssel 

Netherlands 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/318/003 

 

 

13.  BATCH NUMBER 

 

Batch  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE  

 

Revatio 10 mg/ml 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 
 



76 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN:  



77 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Revatio 10 mg/ml powder for oral suspension 

Sildenafil  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Once reconstituted one bottle contains 1.12 g of sildenafil (as citrate) with a final volume of 112 ml. 

Each ml of reconstituted suspension contains 10 mg of sildenafil (as citrate). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains sorbitol. 
See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for oral suspension 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Shake bottle well before use. 

Read the package leaflet before use. 

Oral use. 

 

Reconstitution instructions: 

Tap the bottle to release the powder and remove the cap. 

Add a total of 90 ml of water (3 x 30 ml) strictly following the package leaflet, ensuring the bottle is 

shaken vigorously after adding 60 ml and the remaining 30 ml. Remove the cap again, press the bottle 

adaptor into the neck of the bottle. Note: Expires 30 days after reconstitution.  

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 



78 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

After reconstitution: Store below 30°C or in refrigerator at 2°C to 8°C. Do not freeze. Discard any 

remaining suspension 30 days after reconstitution. 

 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME OF THE MARKETING AUTHORISATION HOLDER OR MARKETING 

AUTHORISATION HOLDER LOGO 

 

Upjohn 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/05/318/003 

 

 

13.  BATCH NUMBER 

 

Batch  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE  

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

 

 



79 

 

 

 

 
 

 

 

 

 
 

 

 

 

 
 

 

 

 

 

 
 

 

 

B. PACKAGE LEAFLET 

 



80 

Package leaflet: Information for the patient 
 

Revatio 20 mg film-coated tablets 

Sildenafil 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

1. What Revatio is and what it is used for 

2. What you need to know before you take Revatio 
3. How to take Revatio 

4. Possible side effects  

5 How to store Revatio 

6. Contents of the pack and other information 

 

 
1. What Revatio is and what it is used for 

 

Revatio contains the active substance sildenafil which belongs to a group of medicines called 

phosphodiesterase type 5 (PDE5) inhibitors.  

Revatio brings down blood pressure in the lungs by widening the blood vessels in the lungs.  
Revatio is used to treat adults and children and adolescents from 1 to 17 years old with high blood 

pressure in the blood vessels in the lungs (pulmonary arterial hypertension).  

 

 

2. What you need to know before you take Revatio 
 

Do not take Revatio:  

 

- if you are allergic to sildenafil or any of the other ingredients of this medicine (listed in section 
6). 

 
- if you are taking medicines containing nitrates, or nitric oxide donors such as amyl nitrate 

(“poppers”). These medicines are often given for relief of chest pain (or “angina pectoris”). 

Revatio can cause a serious increase in the effects of these medicines. Tell your doctor if you are 

taking any of these medicines. If you are not certain, ask your doctor or pharmacist.  

 
- if you are taking riociguat. This drug is used to treat pulmonary arterial hypertension (i.e., high 

blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., high 

blood pressure in the lungs secondary to blood clots). PDE5 inhibitors, such as Revatio have 

been shown to increase the hypotensive effects of this medicine. If you are taking riociguat or 

are unsure tell your doctor. 
 

- if you have recently had a stroke, a heart attack or if you have severe liver disease or very low 
blood pressure (<90/50 mmHg). 

 

- if you are taking a medicine to treat fungal infections such as ketoconazole or itraconazole or 
medicines containing ritonavir (for HIV). 

 



81 

- if you have ever had loss of vision because of a problem with blood flow to the nerve in the eye 
called non-arteritic anterior ischaemic optic neuropathy (NAION). 

 

Warnings and precautions 

Talk to your doctor before taking Revatio if you: 

-  have a disease due to a blocked or narrow vein in the lungs rather than a blocked or narrow 
artery. 

- have a severe heart problem. 
- have a problem with the pumping chambers of your heart  
- have high blood pressure in the blood vessels in the lungs. 
- have low blood pressure at rest. 
- lose a large amount of body fluids (dehydration) which can occur when you sweat a lot or do 

not drink enough liquids. This can happen if you are sick with a fever, vomiting, or diarrhoea. 

- have a rare inherited eye disease (retinitis pigmentosa). 
- have an abnormality of red blood cells (sickle cell anaemia), cancer of blood cells (leukaemia), 

cancer of bone marrow (multiple myeloma), or any disease or deformity of the penis.  

- currently have a stomach ulcer, a bleeding disorder (such as haemophilia) or problems with 
nose bleeds. 

- take medicines for erectile dysfunction. 
 

When used to treat male erectile dysfunction (ED), the following visual side effects have been 

reported with PDE5 inhibitors, including sildenafil at an unknown frequency; partial, sudden, 

temporary, or permanent decrease or loss of vision in one or both eyes. 
 

If you experience sudden decrease or loss of vision, stop taking Revatio and contact your doctor 

immediately (see also section 4). 

 

Prolonged and sometimes painful erections have been reported in men after taking sildenafil. If you 
have an erection, which lasts continuously for more than 4 hours, stop taking Revatio and contact 

your doctor immediately (see also section 4). 

 

Special considerations for patients with kidney or liver problems 

You should tell your doctor if you have kidney or liver problems, as your dose may need to be 
adjusted. 

 

Children 

Revatio should not be given to children below 1 year of age. 

 

Other medicines and Revatio 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

•  Medicines containing nitrates, or nitric oxide donors such as amyl nitrate (“poppers”). These 
medicines are often given for relief of angina pectoris or “chest pain” (see section 2. Before 
you take Revatio) 

•  Tell your doctor or pharmacist if you are already taking riociguat. 

•   Therapies for pulmonary hypertension (e.g. bosentan, iloprost)  

•  Medicines containing St. John’s Wort (herbal medicinal product), rifampicin (used to treat 
bacterial infections), carbamazepine, phenytoin and phenobarbital (used, among others, to 
treat epilepsy)  

•  Blood thinning medicines (for example warfarin) although these did not result in any side 
effect. 

•  Medicines containing erythromycin, clarithromycin, telithromycin (these are antibiotics used 
to treat certain bacterial infections), saquinavir (for HIV) or nefazodone (for mental 
depression), as your dose may need to be adjusted. 



82 

•  Alpha-blocker therapy (e.g. doxazosin) for the treatment of high blood pressure or prostate 
problems, as the combination of the two medicines may cause symptoms resulting in the 

lowering of your blood pressure (e.g. dizziness, light headedness). 

 

Revatio with food and drink 

You should not drink grapefruit juice while you are being treated with Revatio. 

 
Pregnancy and breast-feeding 

If you are pregnant, or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. Revatio should not be used during 

pregnancy unless strictly necessary. 

Revatio should not be given to women of child bearing potential unless using appropriate 
contraceptive methods. 

Revatio passes into your breast milk at very low levels and would not be expected to harm your baby.  

 

Driving and using machines 

Revatio can cause dizziness and can affect vision. You should be aware of how you react to the 
medicine before you drive or use machines.   

 

Revatio contains lactose 

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 

before taking this -medicinal product. 

 
 

3. How to take Revatio 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 

if you are not sure.  
 

For adults, the recommended dose is 20 mg three times a day (taken 6 to 8 hours apart) taken with or 

without food.  

 

Use in children and adolescents 

For children and adolescents aged 1 year to 17 years old, the recommended dose is either 10 mg three 

times a day for children and adolescents ≤ 20 kg or 20 mg three times a day for children and 

adolescents > 20 kg, taken with or without food. Higher doses should not be used in children. This 

medicine should be used only in case of administration of 20 mg three times a day. Other 

pharmaceutical forms may be more appropriate for administration to patients ≤ 20 kg and other 

younger patients who are not able to swallow tablets. 

 

If you take more Revatio than you should 

You should not take more medicine than your doctor tells you to.  

If you take more medicine than you have been told to take contact your doctor immediately. Taking 

more Revatio than you should may increase the risk of known side effects.  

 

If you forget to take Revatio 

If you forget to take Revatio, take a dose as soon as you remember, then continue to take your 

medicine at the usual times. Do not take a double dose to make up for a forgotten dose. 

 
If you stop taking Revatio 

Suddenly stopping your treatment with Revatio may lead to your symptoms getting worse. Do not stop 

taking Revatio unless your doctor tells you to. Your doctor may tell you to reduce the dose over a few 

days before stopping completely. 

 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 



83 

4. Possible side effects  
 

Like all medicines, Revatio can cause side effects, although not everybody gets them. 

 

If you experience any of the following side effects you should stop taking Revatio and contact a doctor 

immediately (see also section 2):  

- if you experience sudden decrease or loss of vision (frequency not known) 
- if you have an erection, which lasts continuously for more than 4 hours. Prolonged and sometimes 

 painful erections have been reported in men after taking sildenafil (frequency not known). 

 

Adults 

Side effects reported very commonly (may affect more than 1 in 10 people) were headache, facial 
flushing, indigestion, diarrhoea and pain in the arms or legs. 

 

Side effects reported commonly (may affect up to 1 in 10 people) included: infection under the skin, 

flu-like symptoms, inflammation of the sinuses, reduced number of red blood cells (anaemia), fluid 

retention, difficulty sleeping, anxiety, migraine, shaking, “pins and needles”-like sensation, burning 
sensation, reduced sense of touch, bleeding at the back of the eye, effects on vision, blurred vision and 

light sensitivity, effects on colour vision, eye irritation, bloodshot eyes /red eyes, vertigo, bronchitis, 

nosebleed, runny nose, cough, stuffy nose, stomach inflammation, gastroenteritis, heartburn, piles, 

abdominal distension, dry mouth, hair loss, redness of the skin, night sweats, muscle aches, back pain 

and increased body temperature. 

 
Side effects reported uncommonly (may affect 1 in 100 people) included: reduced sharpness of vision, 

double vision, abnormal sensation in the eye, penile bleeding, presence of blood in semen and/or 

urine, and breast enlargement in men. 

 

Skin rash and sudden decrease or loss of hearing and decreased blood pressure have also been reported 
at an unknown frequency (frequency cannot be estimated from the available data). 

 

Children and adolescents 

The following serious adverse events have been reported commonly (may affect up to 1 in 10 people); 

pneumonia, heart failure, right heart failure, heart related shock, high blood pressure in the lungs, chest 

pain, fainting, respiratory infection, bronchitis, viral infection in the stomach and intestines, urinary 

tract infections and tooth cavities. 

 

The following serious adverse events were considered to be treatment related and were reported 

uncommonly (may affect up to 1 in 100 people), allergic reaction (such as skin rash, swelling of the 

face, lips and tongue, wheezing, difficulty breathing or swallowing), convulsion, irregular heart-beat, 

hearing impairment, shortness of breath, inflammation of the digestive tract, wheezing due to 

disrupted airflow. 

 

Side effects reported very commonly (may affect more than 1 in 10 people) were headache, vomiting, 

infection of the throat, fever, diarrhoea, flu and nosebleed. 

 

Side effects reported commonly (may affect up to 1 in 10 people) were nausea, increased erections, 

pneumonia and runny nose. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Revatio 



84 

 
Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 

refers to the last day of that month. 

 

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

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 

 

 
6. Contents of the pack and other information 

 

What Revatio contains 

- The active substance is sildenafil. Each tablet contains 20 mg of sildenafil (as the citrate). 
- The other ingredients are: 

Tablet core: microcrystalline cellulose, calcium hydrogen phosphate (anhydrous), 

croscarmellose sodium, magnesium stearate. 

Film coat: hypromellose, titanium dioxide (E171), lactose monohydrate, glycerol triacetate 

 

What Revatio looks like and contents of the pack 
Revatio film-coated tablets are white and round in shape. The tablets are marked with “PFIZER” on 

one side and “RVT 20” on the other. The tablets are provided in blister packs containing 90 tablets,  

90 x 1 tablets as perforated unit dose blisters and in blister packs containing 300 tablets. Not all pack 

sizes may be marketed.  

 
Marketing Authorisation Holder and Manufacturer 

 

Marketing Authorisation Holder:  

Upjohn EESV, Rivium Westlaan 142, 2909 LD Capelle aan den IJssel, Netherlands. 

 

Manufacturer: 
Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France. 

 

For any information about this medicinal product, please contact the local representative of the 

Marketing Authorisation Holder. 

 

België /Belgique / Belgien Lietuva 

Pfizer S.A./N.V.  Pfizer Luxembourg SARL filialas Lietuvoje 

Tél/Tel: +32 (0)2 554 62 11 Tel. +3705 2514000 

  

България Luxembourg/Luxemburg 

Пфайзер Люксембург САРЛ, Клон България Pfizer S.A. 

Тел.: +359 2 970 4333 Tél/Tel: +32 (0)2 554 62 11 

  

Česká republika Magyarország 

Pfizer s.r.o. Pfizer Kft. 

Tel: +420-283-004-111 Tel.: + 36 1 488 37 00 
  

Danmark Malta 

Pfizer ApS Vivian Corporation Ltd. 

Tlf: +45 44 20 11 00 Tel: +356 21344610 

  



85 

Deutschland Nederland 
Pfizer OFG Germany GmbH Pfizer bv 

Tel: +49 (0)800 5500634 Tel: +31 (0)10 406 43 01 

  

Eesti Norge 

Pfizer Luxembourg SARL Eesti filiaal Pfizer AS 

Tel: +372 666 7500 Tlf: +47 67 52 61 00 
  

Ελλάδα Österreich 

UPJOHN HELLAS ΕΠΕ Pfizer Corporation Austria Ges.m.b.H. 

Τηλ: +30 2100 100 002 Tel: +43 (0)1 521 15-0 

  

España Polska 

Pfizer GEP, S.L. Pfizer Polska Sp. z o.o., 
Tel: +34 91 490 99 00 Tel.: +48 22 335 61 00 

  

France Portugal 

Pfizer PFE France Laboratórios Pfizer, Lda. 

Tél: +33 (0)1 58 07 34 40 Tel: +351 21 423 5500 
  

Hrvatska România 

Pfizer Croatia d.o.o. Pfizer România S.R.L. 

Tel: +385 1 3908 777 Tel: +40 21 207 28 00 

  

Ireland Slovenija 

Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free) 

+44 (0)1304 616161 

Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 

farmacevtske dejavnosti, Ljubljana  

 Tel: + 386 (0) 1 52 11 400 

  

Ísland Slovenská republika 

Icepharma hf. Pfizer Luxembourg SARL, organizačná zložka  

Sími: + 354 540 8000 Tel: +421-2-3355 5500 

  
Italia Suomi/Finland 

Pfizer Established Medicine Italy S.r.l. Pfizer Oy 

Tel: +39 06 33 18 21 Puh/Tel: +358 (0)9 43 00 40 

  

Κύπρος Sverige  
GPA Pharmaceuticals Ltd Pfizer AB 

Τηλ: +357 22863100 Tel: + 46 (0)8 550 520 00 

  

Latvija United Kingdom 

Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited 

Tel: +371 670 35 775 Tel: +44 (0)1304 616161 

 

This leaflet was last revised in  

 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu. There are also links to other website about rare diseases and treatments. 

 



86 

 

Package leaflet: Information for the user 

 

Revatio 0.8 mg/ml solution for injection 
Sildenafil 

 

Read all of this leaflet carefully before you are given this medicine because it contains important 

information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

1. What Revatio is and what it is used for 

2. What you need to know before you are given Revatio 

3. How Revatio is given 

4. Possible side effects  
5 How to store Revatio 

6. Contents of the pack and other information 

 

 

1. What Revatio is and what it is used for 
 

Revatio contains the active substance sildenafil which belongs to a group of medicines called 

phosphodiesterase type 5 (PDE5) inhibitors. 

Revatio brings down blood pressure in the lungs by widening the blood vessels in the lungs. 

Revatio is used to treat adults with high blood pressure in the blood vessels in the lungs (pulmonary 
arterial hypertension). 

 

Revatio solution for injection is an alternative formulation of Revatio for patients who temporarily 

cannot take their Revatio tablets. 

 

 
2. What you need to know before you are given Revatio 

 

You should not be given Revatio: 

 

- if you are allergic to sildenafil or any of the other ingredients of this medicine (listed in section 
6). 

 

-  if you are taking medicines containing nitrates, or nitric oxide donors such as amyl nitrate 
(“poppers”). These medicines are often given for relief of chest pain (or “angina pectoris”). 

Revatio can cause a serious increase in the effects of these medicines. Tell your doctor if you are 
taking any of these medicines. If you are not certain, ask your doctor or pharmacist.  

 

- if you are taking riociguat. This drug is used to treat pulmonary arterial hypertension (i.e., high 
blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., high 

blood pressure in the lungs secondary to blood clots). PDE5 inhibitors, such as Revatio have 
been shown to increase the hypotensive effects of this medicine. If you are taking riociguat or 

are unsure tell your doctor. 

 

- if you have recently had a stroke, a heart attack or if you have severe liver disease or very low 
blood pressure (< 90/50 mmHg). 

 



87 

- if you are taking a medicine to treat fungal infections such as ketoconazole or itraconazole or 
medicines containing ritonavir (for HIV). 

 

- if you have ever had loss of vision because of a problem with blood flow to the nerve in the eye 
called non-arteritic anterior ischaemic optic neuropathy (NAION). 

 

Warnings and Precautions 
Talk to your doctor before using Revatio if you: 

- have a disease due to a blocked or narrow vein in the lungs rather than a blocked or narrow 
artery. 

- have a severe heart problem. 
- have a problem with the pumping chambers of your heart 
- have high blood pressure in the blood vessels in the lungs. 
- have low blood pressure at rest. 
- lose a large amount of body fluids (dehydration) which can occur when you sweat a lot or do 

not drink enough liquids. This can happen if you are sick with a fever, vomiting, or diarrhoea. 

- have a rare inherited eye disease (retinitis pigmentosa). 
- have an abnormality of red blood cells (sickle cell anaemia), cancer of blood cells (leukaemia), 

cancer of bone marrow (multiple myeloma), or any disease or deformity of the penis. 

- currently have a stomach ulcer, a bleeding disorder (such as haemophilia) or problems with 
nose bleeds. 

- take medicines for erectile dysfunction. 
 
When used to treat male erectile dysfunction (ED), the following visual side effects have been 

reported with PDE5 inhibitors, including sildenafil at an unknown frequency; partial, sudden, 

temporary, or permanent decrease or loss of vision in one or both eyes. 

If you experience sudden decrease or loss of vision, stop taking Revatio and contact your doctor 

immediately (see also section 4). 
 

Prolonged and sometimes painful erections have been reported in men after taking sildenafil. If you 

have an erection, which lasts continuously for more than 4 hours, stop taking Revatio and contact 

your doctor immediately (see also section 4). 

 
Special considerations for patients with kidney or liver problems 

You should tell your doctor if you have kidney or liver problems, as your dose may need to be 

adjusted. 

 

Children and adolescents 

Revatio should not be given to children and adolescents under the age of 18. 
 

Other medicines and Revatio 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines.  

 

•  Medicines containing nitrates, or nitric oxide donors such as amyl nitrate (“poppers”). These 
medicines are often given for relief of angina pectoris or “chest pain” (see section 2. Before 

you take Revatio). 

•  Tell your doctor or pharmacist if you are already taking riociguat. 

•  Therapies for pulmonary hypertension (e.g. bosentan, iloprost). 
•  Medicines containing St. John’s Wort (herbal medicinal product), rifampicin (used to treat 

bacterial infections), carbamazepine, phenytoin and phenobarbital (used, among others, to 

treat epilepsy).  

•  Blood thinning medicines (for example warfarin) although these did not result in any side 
effects. 

•  Medicines containing erythromycin, clarithromycin, telithromycin (these are antibiotics used 
to treat certain bacterial infections), saquinavir (for HIV) or nefazodone (for mental 

depression), as your dose may need to be adjusted. 



88 

•  Alpha-blocker therapy (e.g. doxazosin) for the treatment of high blood pressure or prostate 
problems, as the combination of the two medicines may cause symptoms of low blood 

pressure (e.g. dizziness, lightheadedness). 

  

Revatio with food and drink 

You should not drink grapefruit juice while you are being treated with Revatio. 

 
Pregnancy and breast-feeding 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. Revatio should not be used during 

pregnancy unless strictly necessary. 

Revatio should not be given to women of child bearing potential unless using appropriate 
contraceptive methods. 

Revatio passes into your breast milk at very low levels and would not be expected to harm your baby. 

 

Driving and using machines 

Revatio can cause dizziness and can affect vision. You should be aware of how you react to the 
medicine before you drive or use machines. 

 

 

3. How Revatio is given 

 

Revatio is given as an intravenous injection and will always be given to you by a doctor or a nurse. 
Your doctor will determine the duration of your treatment and how much Revatio intravenous 

injection you will receive each day and will monitor your response and condition. The usual dose is 

10 mg (corresponding to 12.5 ml) three times a day. 

 

A Revatio intravenous injection will be given to you instead of your Revatio tablets. 
 

If you receive more Revatio than you should 

If you are concerned that you may have been given too much Revatio, tell your doctor or nurse 

immediately. Taking more Revatio than you should may increase the risk of known side effects. 

 
If you miss a dose of Revatio 

As you will be given this medicine under close medical supervision, it is unlikely that a dose would be 

missed. However tell your doctor or pharmacist if you think that a dose has been forgotten.  

A double dose should not be given to make up for a forgotten dose. 

 
If you stop use of Revatio 

Suddenly stopping your treatment with Revatio may lead to your symptoms getting worse. Your 

doctor may reduce the dose over a few days before stopping completely. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 

 

4. Possible side effects  

 

Like all medicines, Revatio can cause side effects, although not everybody gets them. 
 

If you experience any of the following side effects you should stop taking Revatio and contact a doctor 

immediately (see also section 2): 

- if you experience sudden decrease or loss of vision (frequency not known) 

- if you have an erection, which lasts continuously for more than 4 hours. Prolonged and sometimes 

 painful erections have been reported in men after taking sildenafil (frequency not known). 
 



89 

Adults 
Side effects reported in a clinical trial with intravenous Revatio were similar to those reported in 

clinical trials with Revatio tablets. In clinical trials the side effects reported commonly (may affect up 

to 1 in 10 people) were facial flushing, headache, low blood pressure and nausea. 

 

In clinical trials side effects reported commonly (may affect up to 1 in 10 people) by patients with 

pulmonary arterial hypertension were facial flushing and nausea. 
 

In clinical trials with Revatio tablets side effects reported very commonly (may affect more than 1 in 

10 people) were headache, facial flushing, indigestion, diarrhoea and pain in the arms or legs. 

 

Side effects reported commonly (may affect up to 1 in 10 people) included: infection under the skin, 
flu-like symptoms, inflammationof the sinuses, reduced number of red blood cells (anaemia), fluid 

retention, difficulty sleeping, anxiety, migraine, shaking, “pins and needles”-like sensation, burning 

sensation, reduced sense of touch, bleeding at the back of the eye, effects on vision, blurred vision and 

light sensitivity, effects on colour vision, eye irritation, bloodshot eyes /red eyes, vertigo, bronchitis, 

nosebleed, runny nose, cough, stuffy nose, stomach inflammation, gastroenteritis, heartburn, piles, 
abdominal distension, dry mouth, hair loss, redness of the skin, night sweats,  muscle aches, back pain 

and increased body temperature. 

 

Side effects reported uncommonly (may affect upto 1 in 100 people) included: reduced sharpness of 

vision, double vision, abnormal sensation in the eye, penile bleeding, presence of blood in semen 

and/or urine, and breast enlargement in men. 
 

Skin rash and sudden decrease or loss of hearing and decreased blood pressure have also been reported 

at an unknown frequency (frequency cannot be estimated from the available data). 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 
5. How to store Revatio 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the vial label and carton after EXP. 

The expiry date refers to the last day of that month. 
 

Revatio does not require any special storage conditions. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how 

tothrow away medicines you no longer use. These measures will help to protect the environment. 
 

 

6. Contents of the pack and other information 

 

What Revatio contains 

- The active substance is sildenafil. Each ml of solution contains 0.8 mg of sildenafil (as citrate). 
 Each 20 ml vial contains 10 mg sildenafil (as citrate).  

- The other ingredients are glucose and water for injections.   
 



90 

What Revatio looks like and contents of the pack 
Each pack of Revatio solution for injection contains one 20 ml clear glass vial, which is closed with a 

chlorobutyl rubber stopper and an aluminium seal. 

 

Marketing Authorisation Holder and Manufacturer 

 

Marketing Authorisation Holder:  
Upjohn EESV, Rivium Westlaan 142, 2909 LD Capelle aan den IJssel, Netherlands. 

 

Manufacturer: 

Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France. 

 

For any information about this medicinal product, please contact the local representative of the 

Marketing Authorisation Holder. 

 

 

België /Belgique / Belgien Lietuva 

Pfizer S.A./N.V.  Pfizer Luxembourg SARL filialas Lietuvoje 
Tél/Tel: +32 (0)2 554 62 11 Tel. +3705 2514000 

  

България Luxembourg/Luxemburg 

Пфайзер Люксембург САРЛ, Клон България Pfizer S.A. 

Тел.: +359 2 970 4333 Tél/Tel: +32 (0)2 554 62 11 

  

Česká republika Magyarország 
Pfizer s.r.o. Pfizer Kft. 

Tel: +420-283-004-111 Tel.: + 36 1 488 37 00 

  

Danmark Malta 

Pfizer ApS Vivian Corporation Ltd. 

Tlf: +45 44 20 11 00 Tel: +356 21344610 
  

Deutschland Nederland 

Pfizer OFG Germany GmbH Pfizer bv 

Tel: +49 (0)800 5500634 Tel: +31 (0)10 406 43 01 

  
Eesti Norge 

Pfizer Luxembourg SARL Eesti filiaal Pfizer AS 

Tel: +372 666 7500 Tlf: +47 67 52 61 00 

  

Ελλάδα Österreich 

UPJOHN HELLAS ΕΠΕ Pfizer Corporation Austria Ges.m.b.H. 

Τηλ: +30 2100 100 002 Tel: +43 (0)1 521 15-0 

  

España Polska 

Pfizer GEP, S.L. Pfizer Polska Sp. z o.o., 

Tel: +34 91 490 99 00 Tel.: +48 22 335 61 00 

  
France Portugal 

Pfizer PFE France Laboratórios Pfizer, Lda. 

Tél: +33 (0)1 58 07 34 40 Tel: +351 21 423 5500 

  

Hrvatska România 

Pfizer Croatia d.o.o. Pfizer România S.R.L. 

Tel: +385 1 3908 777 Tel: +40 21 207 28 00 

  



91 

Ireland Slovenija 
Pfizer Healthcare Ireland 

Tel: 1800 633 363 (toll free) 

+44 (0)1304 616161 

Pfizer Luxembourg SARL 

Pfizer, podružnica za svetovanje s področja 

farmacevtske dejavnosti, Ljubljana  

 Tel: + 386 (0) 1 52 11 400 

  

Ísland Slovenská republika 

Icepharma hf. Pfizer Luxembourg SARL, organizačná zložka  

Sími: + 354 540 8000 Tel: +421-2-3355 5500 
  

Italia Suomi/Finland 

Pfizer Established Medicine Italy S.r.l. Pfizer Oy 

Tel: +39 06 33 18 21 Puh/Tel: +358 (0)9 43 00 40 

  
Κύπρος Sverige  

GPA Pharmaceuticals Ltd Pfizer AB 

Τηλ: +357 22863100 Tel: + 46 (0)8 550 520 00 

  

Latvija United Kingdom 

Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited 

Tel: +371 670 35 775 Tel: +44 (0)1304 616161 

 

This leaflet was last revised in  

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu. There are also links to other website about rare diseases and treatments. 
 

 

 



92 

Package leaflet: Information for the patient 
 

Revatio 10 mg/ml powder for oral suspension 

Sildenafil 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

1. What Revatio is and what it is used for 

2. What you need to know before you take Revatio 
3. How to take Revatio 

4. Possible side effects  

5 How to store Revatio 

6. Contents of the pack and other information 

 

 
1. What Revatio is and what it is used for 

 

Revatio contains the active substance sildenafil which belongs to a group of medicines called 

phosphodiesterase type 5 (PDE5) inhibitors. 

Revatio brings down blood pressure in the lungs by widening the blood vessels in the lungs. 
Revatio is used to treat adults and children and adolescents from 1 to 17 years old with high blood 

pressure in the blood vessels in the lungs (pulmonary arterial hypertension). 

 

 

2. What you need to know before you take Revatio 
 

Do not take Revatio: 

 

- if you are allergic to sildenafil or any of the other ingredients of this medicine (listed in section 6) 
 

- if you are taking medicines containing nitrates, or nitric oxide donors such as amyl nitrate 
(“poppers”). These medicines are often given for relief of chest pain (or “angina pectoris”). 

Revatio can cause a serious increase in the effects of these medicines. Tell your doctor if you are 

taking any of these medicines. If you are not certain, ask your doctor or pharmacist. 

 

- if you are taking riociguat. This drug is used to treat pulmonary arterial hypertension (i.e., high 
blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., high 

blood pressure in the lungs secondary to blood clots). PDE5 inhibitors, such as Revatio have been 

shown to increase the hypotensive effects of this medicine. If you are taking riociguat or are 

unsure tell your doctor. 

 
- if you have recently had a stroke, a heart attack or if you have severe liver disease or very low 

blood pressure (<90/50 mmHg). 

 

- if you are taking a medicine to treat fungal infections such as ketoconazole or itraconazole or 
medicines containing ritonavir (for HIV). 

 

- if you have ever had loss of vision because of a problem with blood flow to the nerve in the eye 
called non-arteritic anterior ischaemic optic neuropathy (NAION). 



93 

 
Warnings and Precautions 

Talk to your doctor before taking Revatio if you: 

- have a disease due to a blocked or narrow vein in the lungs rather than a blocked or narrow 
artery. 

- have a severe heart problem. 
- have a problem with the pumping chambers of your heart 
- have high blood pressure in the blood vessels in the lungs. 
- have low blood pressure at rest. 
- lose a large amount of body fluids (dehydration) which can occur when you sweat a lot or do 

not drink enough liquids. This can happen if you are sick with a fever, vomiting, or diarrhoea 

- have a rare inherited eye disease (retinitis pigmentosa) 
- have an abnormality of red blood cells (sickle cell anaemia), (cancer of blood cells (leukaemia), 

cancer of bone marrow) (multiple myeloma), or any disease or deformity of the penis. 

- currently have a stomach ulcer, a bleeding disorder (such as haemophilia) or problems with 
nose bleeds. 

- take medicines for erectile dysfunction. 
 

When used to treat male erectile dysfunction (ED), the following visual side effects have been 

reported with PDE5 inhibitors, including sildenafil at an unknown frequency; partial, sudden, 

temporary, or permanent decrease or loss of vision in one or both eyes. 

If you experience sudden decrease or loss of vision, stop taking Revatio and contact your doctor 

immediately (see also section 4). 
 

Prolonged and sometimes painful erections have been reported in men after taking sildenafil. If you 

have an erection, which lasts continuously for more than 4 hours, stop taking Revatio and contact 

your doctor immediately (see also section 4). 

 
Special considerations for patients with kidney or liver problems 

You should tell your doctor if you have kidney or liver problems, as your dose may need to be 

adjusted.  

 

Children 
Revatio should not be given to children below 1 year of age.  

 

Other medicines and Revatio 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

• Medicines containing nitrates, or nitric oxide donors such as amyl nitrate (“poppers”). These 
medicines are often given for relief of angina pectoris or “chest pain” (see section 2. Before 

you take Revatio) 

• Tell your doctor or pharmacist if you are already taking riociguat. 

• Therapies for pulmonary hypertension (e.g. bosentan, iloprost) 
• Medicines containing St. John’s Wort (herbal medicinal product), rifampicin (used to treat 

bacterial infections), carbamazepine, phenytoin and phenobarbital (used, among others, to 

treat epilepsy) 

• blood thinning medicines (for example warfarin) although these did not result in any side 
effect 

• Medicines containing erythromycin, clarithromycin, telithromycin (these are antibiotics used 
to treat certain bacterial infections), saquinavir (for HIV) or nefazodone (for mental 

depression), as your dose may need to be adjusted. 

• Alpha-blocker therapy (e.g. doxazosin) for the treatment of high blood pressure or prostate 
problems, as the combination of the two medicines may cause symptoms of low blood 
pressure (e.g. dizziness, light headedness). 

 

Revatio with food and drink 



94 

You should not drink grapefruit juice while you are being treated with Revatio.  
 

Pregnancy and breast-feeding 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. Revatio should not be used during 

pregnancy unless strictly necessary. 

Revatio should not be given to women of child bearing potential unless using appropriate 
contraceptive methods. 

Revatio passes into your breast milk at very low levels and would not be expected to harm your baby. 

 

Driving and using machines 

Revatio can cause dizziness and can affect vision. You should be aware of how you react to the 
medicine before you drive or use machines. 

 

Revatio contains sorbitol 

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 

before taking this medicinal product. 
 

 

3. How to take Revatio 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 

if you are not sure. 
 

For adults, the recommended dose is 20 mg three times a day (taken 6 to 8 hours apart) taken with or 

without food.  

 

Use in children and adolescents 

For children and adolescents aged 1 year to 17 years old, the recommended dose is either 10 mg (1 ml 

of oral suspension) three times a day for children and adolescents weighing 20 kg or under, or 20 mg 

(2 ml of oral suspension) three times a day for children and adolescents weighing over 20 kg, taken 

with or without food. Higher doses should not be used in children. 

 

The oral suspension must be shaken vigorously for a minimum of 10 seconds before use. 

 

Instructions to reconstitute the oral suspension 

It is recommended that your pharmacist reconstitutes (makes up) the oral suspension before giving it 
to you. 

 

If reconstituted, the oral suspension is in a liquid form. If the powder is not reconstituted, you should 

reconstitute the oral suspension by following the instructions below. 

 

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

 

1. Tap the bottle to release the powder. 
2. Remove the cap. 
3. Measure 30 ml of water by filling the measuring cup (included in the carton) to the marked 

line then pour the water into the bottle. Using the cup measure another 30 ml of water and add 

this to the bottle (figure 1). 



95 

 
figure 1 

 
 

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

 
figure 2 
 

 

5. Remove the cap. 
6. Using the cup measure another 30 ml of water and add this to the bottle. You should always 

add a total of 90 ml (3 x 30 ml) of water irrespective of the dose you are taking (figure 3). 

 
figure 3 

 
 

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



96 

 
figure 4 

 
 

8. Remove the cap. 
9. Press the bottle adaptor into the neck of the bottle (as shown on figure 5 below). The adaptor 

is provided so that you can fill the oral dosing syringe with medicine from the bottle. Replace 

the cap on the bottle. 

 
figure 5 

 

 

10. Write the date of expiry of the reconstituted oral suspension on the bottle label (the date of 
expiry of the reconstituted oral suspension is 30 days from the date of reconstitution). Any 

unused oral suspension should be discarded or returned to your pharmacist after this date.  
 

Instructions for use  

Your pharmacist should advise you how to measure the medicine using the oral dosing syringe 

provided in the pack. Once reconstituted, the oral suspension should only be administered using the 

oral dosing syringe supplied with each pack. Please see instructions below before using the oral 

suspension. 
 

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



97 

 
figure 6 

 

 

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

 
figure 7 

 

 



98 

3. Turn the bottle upside down while holding the oral dosing syringe in place. Slowly pull back 
the plunger of the oral dosing syringe to the graduation mark that marks the dose for you 

(withdrawing 1 ml provides a 10 mg dose, withdrawing 2 ml provides a 20 mg dose). To 

measure the dose accurately, the top edge of the plunger should be lined up with the 

appropriate graduated mark on the oral dosing syringe (figure 8). 

 

 
figure 8 

 

 

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

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

6. Put the tip of the oral dosing syringe into the mouth. Point the tip of the oral dosing syringe 
towards the inside of the cheek. SLOWLY push down the plunger of the oral dosing syringe. 

Do not squirt the medicine out quickly. If the medicine is to be given to a child, make sure the 

child is sitting, or is held, upright before giving the medicine (figure 9). 
 

 
figure 9 

 
 

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

 
Cleaning and storing the syringe: 

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

parts in water. 

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

medicine. 
 



99 

If you take more Revatio than you should 

You should not take more medicine than your doctor tells you to. 

If you take more medicine than you have been told to take contact your doctor immediately. Taking 

more Revatio than you should may increase the risk of known side effects. 

  

If you forget to take Revatio 

If you forget to take Revatio, take a dose as soon as you remember, then continue to take your 

medicine at the usual times. Do not take a double dose to make up for a forgotten dose. 

 

If you stop taking Revatio 

Suddenly stopping your treatment with Revatio may lead to your symptoms getting worse. Do not stop 
taking Revatio unless your doctor tells you to. Your doctor may tell you to reduce the dose over a few 

days before stopping completely. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 
 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 
If you experience any of the following side effects you should stop taking Revatio and contact a doctor 

immediately (see also section 2): 

- if you experience sudden decrease or loss of vision (frequency not known) 

- if you have an erection, which lasts continuously for more than 4 hours. Prolonged and sometimes 

 painful erections have been reported in men after taking sildenafil (frequency not known). 

 
Adults 

Side effects reported very commonly (may affect more than 1 in 10 people) were headache, facial 

flushing, indigestion, diarrhoea and pain in the arms or legs. 

 

Side effects reported commonly (may affect up to 1 in 10 people) included: infection under the skin, 
flu-like symptoms, inflammation of the sinuses, reduced number of red blood cells (anaemia), fluid 

retention, difficulty sleeping, anxiety, migraine, shaking, “pins and needles”-like sensation, burning 

sensation, reduced sense of touch, bleeding at the back of the eye, effects on vision, blurred vision and 

light sensitivity, effects on colour vision, eye irritation, bloodshot eyes /red eyes, vertigo, bronchitis, 

nosebleed, runny nose, cough, stuffy nose, stomach inflammation, gastroenteritis, heartburn, piles, 
abdominal distension, dry mouth, hair loss, redness of the skin, night sweats, muscle aches, back pain 

and increased body temperature. 

 

Side effects reported uncommonly (may affect up to 1 in 100 people) included: reduced sharpness of 

vision, double vision, abnormal sensation in the eye, penile bleeding, presence of blood in semen 

and/or urine, and breast enlargement in men.  
 

Skin rash and sudden decrease or loss of hearing and decreased blood pressure have also been reported 

at an unknown frequency (frequency cannot be estimated from the available data). 

 

Children and adolescents 

The following serious adverse events have been reported commonly (may affect up to 1 in 10 people); 

pneumonia, heart failure, right heart failure, heart related shock, high blood pressure in the lungs, chest 

pain, fainting, respiratory infection, bronchitis, viral infection in the stomach and intestines, urinary 

tract infections and tooth cavities. 

 

The following serious adverse events were considered to be treatment related and were reported 

uncommonly (may affect up to 1 in 100 people), allergic reaction (such as skin rash, swelling of the 

face, lips and tongue, wheezing, difficulty breathing or swallowing), convulsion, irregular heart-beat, 



100 

hearing impairment, shortness of breath, inflammation of the digestive tract, wheezing due to 

disrupted airflow. 

 

Side effects reported very commonly (may affect more than 1 in 10 people) were headache, vomiting, 

infection of the throat, fever, diarrhoea, flu and nosebleed. 

 

Side effects reported commonly (may affect up to 1 in 10 people) were nausea, increased erections, 

pneumonia and runny nose. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 
5. How to store Revatio 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the bottle after ‘EXP’. The expiry 
date refers to the last day of that month. 

 

Powder 

Do not store above 30°C. 

Store in the original package in order to protect from moisture. 
 

Reconstituted oral suspension 

Store below 30°C or in refrigerator at 2ºC to 8°C. Do not freeze. Any remaining oral suspension 

should be discarded 30 days after reconstitution. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Revatio contains 

- The active substance is sildenafil (as sildenafil citrate). 
After reconstitution, each ml of the oral suspension contains 10 mg of sildenafil (as citrate) 

One bottle of reconstituted oral suspension (112 ml) contains 1.12 g of sildenafil (as citrate) 

 

- The other ingredients are: Powder for oral suspension: sorbitol, citric acid anhydrous, sucralose, 
sodium citrate, xanthan gum, titanium dioxide (E171), sodium benzoate (E211), silica, colloidal 

anhydrous; Grape flavour: maltodextrin, grape juice concentrate, gum acacia, pineapple juice 
concentrate, citric acid anhydrous, natural flavouring 

 

What Revatio looks like and contents of the pack 

Revatio is supplied as a white to off-white powder for oral suspension providing a white, grape 

flavoured oral suspension when reconstituted with water. 
One 125 ml amber glass bottle (with a polypropylene screw cap) contains 32.27 g of powder for oral 

suspension. 

 

Once reconstituted the bottle contains 112 ml of oral suspension, of which 90 ml is intended for dosing 

and administration. 

 



101 

Pack size: 1 bottle 

 

Each pack also contains a polypropylene measuring cup (graduated to indicate 30 ml), polypropylene 

oral dosing syringe (3 ml) with HDPE plunger and a LDPE press-in bottle adaptor. 

 
Marketing Authorisation Holder and Manufacturer 

 

Marketing Authorisation Holder  

Upjohn EESV, Rivium Westlaan 142, 2909 LD Capelle aan den IJssel, Netherlands. 

 

Manufacturer 
Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France. 

 

For any information about this medicinal product, please contact the local representative of the 

Marketing Authorisation Holder. 

 

België /Belgique / Belgien Lietuva 

Pfizer S.A./N.V.  Pfizer Luxembourg SARL filialas Lietuvoje 
Tél/Tel: +32 (0)2 554 62 11 Tel. +3705 2514000 

  

България Luxembourg/Luxemburg 

Пфайзер Люксембург САРЛ, Клон България Pfizer S.A. 

Тел.: +359 2 970 4333 Tél/Tel: +32 (0)2 554 62 11 

  

Česká republika Magyarország 
Pfizer s.r.o. Pfizer Kft. 

Tel: +420-283-004-111 Tel.: + 36 1 488 37 00 

  

Danmark Malta 

Pfizer ApS Vivian Corporation Ltd. 

Tlf: +45 44 20 11 00 Tel: +356 21344610 

  
Deutschland Nederland 

Pfizer OFG Germany GmbH Pfizer bv 

Tel: +49 (0)800 5500634 Tel: +31 (0)10 406 43 01 

  

Eesti Norge 
Pfizer Luxembourg SARL Eesti filiaal Pfizer AS 

Tel: +372 666 7500 Tlf: +47 67 52 61 00 

  

Ελλάδα Österreich 

UPJOHN HELLAS ΕΠΕ Pfizer Corporation Austria Ges.m.b.H. 

Τηλ: +30 2100 100 002 Tel: +43 (0)1 521 15-0 

  
España Polska 

Pfizer GEP, S.L. Pfizer Polska Sp. z o.o., 

Tel: +34 91 490 99 00 Tel.: +48 22 335 61 00 

  

France Portugal 

Pfizer PFE France Laboratórios Pfizer, Lda. 
Tél: +33 (0)1 58 07 34 40 Tel: +351 21 423 5500 

  

Hrvatska România 

Pfizer Croatia d.o.o. Pfizer România S.R.L. 

Tel: +385 1 3908 777 Tel: +40 21 207 28 00 

  



102 

Ireland Slovenija 
Pfizer Healthcare Ireland 

Tel: 1800 633 363 (toll free) 

+44 (0)1304 616161 

Pfizer Luxembourg SARL 

Pfizer, podružnica za svetovanje s področja 

farmacevtske dejavnosti, Ljubljana  

 Tel: + 386 (0) 1 52 11 400 

  

Ísland Slovenská republika 

Icepharma hf. Pfizer Luxembourg SARL, organizačná zložka  

Sími: + 354 540 8000 Tel: +421-2-3355 5500 
  

Italia Suomi/Finland 

Pfizer Established Medicine Italy S.r.l. Pfizer Oy 

Tel: +39 06 33 18 21 Puh/Tel: +358 (0)9 43 00 40 

  
Κύπρος Sverige  

GPA Pharmaceuticals Ltd Pfizer AB 

Τηλ: +357 22863100 Tel: + 46 (0)8 550 520 00 

  

Latvija United Kingdom 

Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited 

Tel: +371 670 35 775 Tel: +44 (0)1304 616161 

 

This leaflet was last revised in  

 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu. There are also links to other website about rare diseases and treatments. 

 

  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET