Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
- 1. NAME OF THE MEDICINAL PRODUCT
1.NAME OF THE MEDICINAL PRODUCT
Revatio 20 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each
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
White, round, biconvex
4.CLINICAL PARTICULARS
4.1Therapeutic 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).
4.2Posology 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.
Patients using other medicinal products
In general, any dose adjustment should be administered only after a careful
Special populations
Elderly (≥ 65 years)
Dose adjustments are not required in elderly patients. Clinical efficacy as measured by
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
Hepatic impairment
Initial dose adjustments are not required in patients with hepatic impairment
Revatio is contraindicated in patients with severe hepatic impairment
Paediatric population
The safety and efficacy of Revatio in children below 1 year of age has not been established. No data are available.
Discontinuation of treatment
Limited data suggests 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.
4.3Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
The
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
The safety of sildenafil has not been studied in the following
Severe hepatic impairment,
Recent history of stroke or myocardial infarction,
Severe hypotension (blood pressure < 90/50 mmHg) at initiation.
4.4Special 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
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
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
assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result (see section 4.8).
Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of
Visual events
Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of
Caution is advised when sildenafil is administered to patients taking an
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
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.
No data are available with sildenafil in patients with pulmonary hypertension associated with pulmonary
Galactose intolerance
Lactose monohydrate is present in the tablet film coat. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
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
4.5Interaction 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
The efficacy and safety of sildenafil
The safety and efficacy of sildenafil when
Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when
CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the
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.
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
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
The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that
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.
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
In vivo studies
No significant interactions were shown when sildenafil (50 mg) was
Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.
No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dl.
In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50 % increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from a study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) indicated an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with
In a specific interaction study, where sildenafil (100 mg) was
In three specific
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
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.
4.6Fertility, 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.
It is not known whether sildenafil enters the breast milk. Revatio should not be administered to
Fertility
4.7Effects 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.
4.8Undesirable effects
Summary of the safety profile
In the pivotal
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
(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
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
In the
Tabulated list of adverse reactions
Adverse reactions which occurred in > 1 % of
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
MedDRA system organ class (V.14.0) | Adverse reaction |
Infections and infestations |
|
Common | cellulitis, influenza, bronchitis, |
Blood and lymphatic system disorders | sinusitis, rhinitis, gastroenteritis |
| |
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 |
Eye disorders | sensation, hypoaesthesia |
| |
Common | retinal haemorrhage, visual |
| impairment, vision blurred, |
| photophobia, chromatopsia, cyanopsia, |
| eye irritation, ocular hyperaemia |
Uncommon | visual acuity reduced, diplopia, |
Not known | abnormal sensation in eye |
| neuropathy (NAION)*, Retinal |
| vascular occlusion*, Visual field |
Ear and labyrinth disorders | defect* |
| |
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 |
Skin and subcutaneous tissue disorders | distension, dry mouth |
| |
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 | haematuria |
Uncommon | |
Reproductive system and breast disorders | penile haemorrhage, haematospermia, |
Uncommon | |
| 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
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
The most common adverse reactions reported across the duration of the
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.
4.9Overdose
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
5.1Pharmacodynamic 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
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
Clinical efficacy and safety
Efficacy in adult patients with pulmonary arterial hypertension (PAH)
A randomised,
68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range:
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
The primary efficacy endpoint was the change from baseline at week 12 in
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
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.
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).
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,
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,
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
≥ 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
Patients enrolled into the epoprostenol
Efficacy and safety in adult patients with PAH (when used in combination with bosentan)
A randomized,
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:
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
A total of 234 subjects aged 1 to 17 years were treated in a randomized,
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,
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
The primary endpoint was the
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 | 3.81 | |
(n=24) | 11.33 | 1.72, 20.94 |
Medium dose | ||
(n=26) | 7.98 | |
High dose | ||
(n=27) | 7.71 | |
Combined dose groups | ||
(n=77) | (p = 0.056) |
|
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
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
During the conduct of the study, there were a total of 42 deaths reported, whether on treatment or reported as part of the survival
Peak VO2 was assessed 1 year after the start of the
The European Medicines Agency has deferred the obligation to submit the results of studies with Revatio in newborns with pulmonary arterial hypertension (see section 4.2 for information on paediatric use).
5.2Pharmacokinetic properties
Absorption
- Sildenafil actavis - sildenafil
- Granpidam - sildenafil citrate
- Vizarsin - sildenafil
- Sildenafil teva - sildenafil
- Sildenafil ratiopharm - sildenafil
Prescription drugs listed. Substance: "Sildenafil"
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
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
Biotransformation
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from
Elimination
The total body clearance of sildenafil is 41 l/h with a resultant terminal phase
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
Renal insufficiency
In volunteers with mild to moderate renal impairment (creatinine clearance =
Hepatic insufficiency
In volunteers with mild to moderate hepatic cirrhosis
was reduced, resulting in increases in AUC (85 %) and Cmax (47 %) compared to
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
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
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.
5.3Preclinical safety data
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
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
6.1List of excipients
Tablet core:
Microcrystalline cellulose
Calcium hydrogen phosphate (anhydrous)
Croscarmellose sodium
Magnesium stearate
Film coat:
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate
Glycerol triacetate
6.2Incompatibilities
Not applicable.
6.3Shelf life
5 years.
6.4Special precautions for storage
Do not store above 30°C. Store in the original package in order to protect from moisture.
6.5Nature 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.
6.6Special precautions for disposal and other handling
No special requirements for disposal.
7.MARKETING AUTHORISATION HOLDER
Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom.
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
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
Patients using other medicinal products
In general, any dose adjustment should be administered only after a careful
Special populations
Elderly (≥ 65 years)
Dose adjustments are not required in elderly patients. Clinical efficacy as measured by
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
Hepatic impairment
Initial dose adjustments are not required in patients with hepatic impairment
Revatio is contraindicated in patients with severe hepatic impairment
Paediatric population
Revatio solution for injection is not recommended for use in children below 18 years due to insufficient data on safety and efficacy.
Discontinuation of treatment
Limited data suggests that the abrupt discontinuation of oral Revatio is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified monitoring is recommended during the discontinuation period.
Method of administration
Revatio solution for injection is for intravenous use as a bolus injection.
See section 6.6 for instructions of use.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
The
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
The safety of sildenafil has not been studied in the following
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
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
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
Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of
Visual events
Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of
Caution is advised when sildenafil is administered to patients taking an
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
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.
No data are available with sildenafil in patients with pulmonary hypertension associated with pulmonary
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
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.
Effects of other medicinal products on intravenous sildenafil
Predictions based on a pharmacokinetic model suggest that
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
The efficacy and safety of sildenafil
The safety and efficacy of sildenafil when
Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when
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
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.
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
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
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
The population pharmacokinetic analysis in pulmonary arterial hypertension patients receiving oral sildenafil suggested that
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.
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
In vivo studies
No significant interactions were shown when oral sildenafil (50 mg) was
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
In a specific interaction study, where oral sildenafil (100 mg) was
In three specific
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
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.
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. It is not known whether sildenafil enters the breast milk. Revatio should not be administered to
Fertility
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
Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability and pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus injection to patients with Pulmonary Arterial Hypertension (PAH) who were already receiving and stable on oral Revatio 20 mg three times per day.
A total of 10 PAH subjects enrolled and completed the study. The mean postural changes in systolic and diastolic blood pressure over time were small (< 10 mmHg) and returned towards baseline beyond 2 hours. No symptoms of hypotension were associated with these changes. The mean changes in heart rate were clinically insignificant. Two subjects experienced a total of 3 adverse reactions (flushing, flatulence and hot flush). There was one serious adverse reaction in a subject with severe ischaemic cardiomyopathy who experienced ventricular fibrillation and death 6 days post study. It was judged to be unrelated to the study medicinal product.
Oral administration
In the pivotal
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
(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
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
In the
Tabulated list of adverse reactions
Adverse reactions which occurred in > 1 % of
( 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
MedDRA system organ class (V.14.0) | Adverse reaction |
Infections and infestations |
|
Common | cellulitis,influenza, bronchitis, |
Blood and lymphatic system disorders | sinusitis, rhinitis, gastroenteritis |
| |
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 |
Eye disorders | sensation, hypoaesthesia |
| |
Common | retinal haemorrhage, visual |
| impairment, vision blurred, |

| photophobia, chromatopsia, cyanopsia, |
| eye irritation, ocular hyperaemia |
Uncommon | visual acuity reduced, diplopia, |
Not known | abnormal sensation in eye |
| neuropathy (NAION)*, Retinal |
| vascular occlusion*, Visual field |
Ear and labyrinth disorders | defect* |
| |
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 |
Skin and subcutaneous tissue disorders | distension, dry mouth |
| |
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, |
Not known | gynaecomastia |
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.
- Viagra - Pfizer Limited
- Vfend - Pfizer Limited
- Nimenrix - Pfizer Limited
- Sutent - Pfizer Limited
- Duavive - Pfizer Limited
- Prevenar 13 - Pfizer Limited
Prescription drugs listed. Manufacturer: "Pfizer Limited"
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.
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
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
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
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,
(< 10 mmHg) and returned towards baseline beyond 2 hours.
Efficacy of oral sildenafil in adult patients with pulmonary arterial hypertension (PAH)
A randomised,
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
The primary efficacy endpoint was the change from baseline at week 12 in
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
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.
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).
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,
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,
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
≥ 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
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 %).
Patients enrolled into the epoprostenol
Efficacy and safety in adult patients with PAH (when used in combination with bosentan)
A randomized,
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:
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).
5.2 Pharmacokinetic properties
Absorption
The mean absolute oral bioavailability for sildenafil is 41 % (range
Cmax, CL and AUC
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
Biotransformation
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from
those observed following oral dosing. At steady state plasma concentrations of
Elimination
The total body clearance of sildenafil is 41 l/h with a resultant terminal phase
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
Renal insufficiency
In volunteers with mild to moderate renal impairment (creatinine clearance =
Hepatic insufficiency
In volunteers with mild to moderate hepatic cirrhosis
was reduced, resulting in increases in AUC (85 %) and Cmax (47 %) compared to
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
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
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
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.
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
Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom.

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
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
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).
Patients using other medicinal products
In general, any dose adjustment should be administered only after a careful
Special populations
Elderly (≥ 65 years)
Dose adjustments are not required in elderly patients. Clinical efficacy as measured by
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
Hepatic impairment
Initial dose adjustments are not required in patients with hepatic impairment
Revatio is contraindicated in patients with severe hepatic impairment
Paediatric population
The safety and efficacy of Revatio in children below 1 year of age has not been established. No data are available.
Discontinuation of treatment
Limited data suggests 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 constituted oral suspension (a white, grape flavoured oral suspension) should be taken approximately 6 to 8 hours apart with or without food.
Before withdrawing the required dose, shake the bottle vigorously for a minimum of 10 seconds.
For instructions on constitution 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.
The
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
The safety of sildenafil has not been studied in the following
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
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
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
Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of
Visual events
Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of
Caution is advised when sildenafil is administered to patients taking an
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
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.
No data are available with sildenafil in patients with pulmonary hypertension associated with pulmonary
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).
Concomitant use with other PDE5 inhibitors
The safety and efficacy of sildenafil when
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
The efficacy and safety of sildenafil
The safety and efficacy of sildenafil when
Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when
CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the
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.
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
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
The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that
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.
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
In vivo studies
No significant interactions were shown when sildenafil (50 mg) was
Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.
No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg).
- Sildenafil teva - G04BE03
- Vizarsin - G04BE03
- Granpidam - G04BE03
- Sildenafil ratiopharm - G04BE03
- Sildenafil actavis - G04BE03
Prescription drugs listed. ATC Code: "G04BE03"
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
In a specific interaction study, where sildenafil (100 mg) was
In three specific
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
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.
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.
It is not known whether sildenafil enters the breast milk. Revatio should not be administered to
Fertility
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
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
(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
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
In the
Tabulated list of adverse reactions
Adverse reactions which occurred in > 1 % of
Reports from
MedDRA system organ class (V.14.0) | Adverse reaction |
Infections and infestations |
|
Common | cellulitis, influenza, bronchitis, |
Blood and lymphatic system disorders | sinusitis, rhinitis, gastroenteritis |
| |
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 |
Eye disorders | sensation, hypoaesthesia |
| |
Common | retinal haemorrhage, visual |
| impairment, vision blurred, |
| photophobia, chromatopsia, cyanopsia, |
| eye irritation, ocular hyperaemia |
Uncommon | visual acuity reduced, diplopia, |
Not known | abnormal sensation in eye |
| neuropathy (NAION)*, Retinal |
| vascular occlusion*, Visual field |
Ear and labyrinth disorders | defect* |
| |
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 |
Skin and subcutaneous tissue disorders | distension, dry mouth |
| |
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, |
Not known | gynaecomastia |
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
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
The most common adverse reactions reported across the duration of the
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.
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
Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mm Hg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mm Hg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen.
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported.
In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to
baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.
Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the
Clinical efficacy and safety
Efficacy in adult patients with pulmonary arterial hypertension (PAH)
A randomised,
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
The primary efficacy endpoint was the change from baseline at week 12 in
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
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.
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).
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,
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,
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
≥ 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
Patients enrolled into the epoprostenol
assessed for a minimum of 3 years. In this population,
Efficacy and safety in adult patients with PAH (when used in combination with bosentan)
A randomized,
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:
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
A total of 234 subjects aged 1 to 17 years were treated in a randomized,
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,
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
The primary endpoint was the
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 | 3.81 | |
(n=24) | 11.33 | 1.72, 20.94 |
Medium dose | ||
(n=26) | 7.98 | |
High dose | ||
(n=27) | 7.71 | |
Combined dose groups | ||
(n=77) | (p = 0.056) |
|
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
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
During the conduct of the study, there were a total of 42 deaths reported, whether on treatment or reported as part of the survival
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
The European Medicines Agency has deferred the obligation to submit the results of studies with Revatio in newborns with pulmonary arterial hypertension (see section 4.2 for information on paediatric use).
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
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
Biotransformation
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from
Elimination
The total body clearance of sildenafil is 41 l/h with a resultant terminal phase
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
Renal insufficiency
In volunteers with mild to moderate renal impairment (creatinine clearance =
Hepatic insufficiency
In volunteers with mild to moderate hepatic cirrhosis
was reduced, resulting in increases in AUC (85 %) and Cmax (47 %) compared to
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
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
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
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
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
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
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 constitutes 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).
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).
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 constituted the powder provides a white grape flavoured oral suspension. Write the date of expiry of the constituted oral suspension on the bottle label (the date of expiry of the

constituted oral suspension is 30 days from the date of constitution). Any unused oral suspension should be discarded or returned to your pharmacist after this date.
Instructions for use
1.Shake the closed bottle of constituted oral suspension vigorously for a minimum of 10 seconds before use. Remove the cap (figure 6).
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).

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.
7. MARKETING AUTHORISATION HOLDER
Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom.

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
- Regranex
- Optruma
- Levetiracetam actavis group
- Tobi podhaler
- Fendrix
- Memantine accord
Prescription drugs listed:
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
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