Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form due to the hypotensive effects of nitrates (see section 5.1).
The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).
Combination with the most potent of the CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) (see section 4.5).
Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4).
The safety of sildenafil has not been studied in the following sub-groups of patients, and its use is therefore contraindicated:
No clinical data is available for sildenafil IV administration in patients who are clinically or haemodynamically unstable. Its use is accordingly not recommended in these patients.
The efficacy of Revatio has not been established in patients with severe pulmonary arterial hypertension (functional class IV). If the clinical situation deteriorates, therapies that are recommended at the severe stage of the disease (eg, epoprostenol) should be considered (see section 4.2).
The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO functional class I pulmonary arterial hypertension.
Studies with sildenafil have been performed in forms of pulmonary arterial hypertension related to primary (idiopathic), connective tissue disease associated or congenital heart disease associated forms of PAH (see section 5.1). The use of sildenafil in other forms of PAH is not recommended.
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.
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)
In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors.
Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).
Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result (see section 4.8).
Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported more commonly by patients receiving Revatio than those receiving placebo leading to the premature termination of this study.
Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual defect, the treatment should be stopped immediately and alternative treatment should be considered (see section 4.3).
Caution is advised when sildenafil is administered to patients taking an alpha-blocker as the co-administration may lead to symptomatic hypotension in susceptible individuals (see section 4.5). In order to minimise the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms.
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these patients only after careful benefit-risk assessment.
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 veno-occlusive disease. However, cases of life threatening pulmonary oedema have been reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.
The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.5 and 5.1).
The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, including Viagra, has not been studied in PAH patients and such concomitant use is not recommended (see section 4.5).
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.
Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4 inhibitors should be less than observed after oral sildenafil administration. The magnitude of the interaction is expected to be reduced for intravenous sildenafil, as interactions for oral sildenafil are due, at least in part, to effects on oral first pass metabolism.
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.
Co-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections 4.8 and 5.1).
The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg, ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.
The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients (see section 4.4).
Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on oral sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43% and 66% higher, respectively, compared to patients not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at an oral dose of 80mg three times a day compared to the exposure at an oral dose of 20mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, ketoconazole, itraconazole, ritonavir).
CYP3A4 inducers seemed to have a substantial impact on the oral pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with CYP3A4 inducer bosentan.
Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 125mg twice daily with oral sildenafil 80mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63% decrease of sildenafil AUC. A population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials including a 12 week study to assess the efficacy and safety of oral sildenafil 20mg three times a day when added to a stable dose of bosentan (62.5mg – 125mg twice a day) indicated a decrease in sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see sections 4.4 and 5.1).
Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine.
Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500mg twice daily) with oral sildenafil (100mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1,000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml when sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200mg three times a day) with oral sildenafil (100mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. For dose recommendations, see section 4.2.
When a single 100mg dose of oral sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500mg 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 (500mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of oral sildenafil or its principal circulating metabolite. No dose adjustment is required. Cimetidine (800mg), a cytochrome P450 inhibitor and a non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with oral sildenafil (50mg) to healthy volunteers. No dose adjustment is required.
The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone) are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors like saquinavir or erythromycin), a seven-fold increase in exposure is assumed. Therefore dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).
The population pharmacokinetic analysis in pulmonary arterial hypertension patients receiving oral sildenafil suggested that co-administration of beta-blockers in combination with CYP3A4 substrates might result in an additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.
Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of oral sildenafil. No dose adjustment is required but the concomitant use of sildenafil and grapefruit juice is not recommended. Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the oral bioavailability of sildenafil.
Co-administration of oral contraceptives (ethinyloestradiol 30μg and levonorgestrel 150μg) did not affect the oral pharmacokinetics of sildenafil.
Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with sildenafil (see section 4.3).
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM).
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.
No significant interactions were shown when oral sildenafil (50mg) was co-administered with tolbutamide (250mg) or warfarin (40mg), both of which are metabolised by CYP2C9.
Oral sildenafil had no significant effect on atorvastatin exposure (AUC increased 11%), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.
No interactions were observed between sildenafil (100mg single oral dose) and acenocoumarol.
Oral sildenafil (50mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150mg).
Oral sildenafil (50mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80mg/dl.
In a study of healthy volunteers oral sildenafil at steady state (80mg three times a day) resulted in a 50% increase in bosentan AUC (125mg twice daily). A population pharmacokinetic analysis of data from a study of adult PAH patients on background bosentan therapy (62.5mg-125mg twice a day) indicated an increase (20% (95% CI: 9.8-30.8)) of bosentan AUC with co-administration of steady- state sildenafil (20mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-administered with 80mg sildenafil three times a day (see sections 4.4 and 5.1).
In a specific interaction study, where oral sildenafil (100mg) was co-administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone to healthy volunteers.
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4mg and 8mg) and oral sildenafil (25mg, 50mg, or 100mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 4.4).
Sildenafil (100mg single oral dose) did not affect the steady state pharmacokinetics of the HIV protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.
Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated (see section 4.3).
Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).
Oral sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30μg and levonorgestrel 150μg).
Interaction studies have only been performed in adults.
Due to lack of data on effects of Revatio in pregnant women, Revatio is not recommended for women of childbearing potential unless also using appropriate contraceptive measures.
There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate 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.
There are no adequate and well controlled studies in lactating women. Data from one lactating woman indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk at very low levels. No clinical data are available regarding adverse events in breast-fed infants, but amounts ingested would not be expected to cause any adverse effects. Prescribers should carefully assess the mother’s clinical need for sildenafil and any potential adverse effects on the breast-fed child.
Non-clinical data revealed no special hazard for humans based on conventional studies of fertility (see section 5.3).
Revatio has moderate influence on the ability to drive and use machines.
As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they might be affected by Revatio, before driving or using machines.
Adverse reactions that resulted from intravenous Revatio use are similar to those associated with oral Revatio use. Since there are limited data for intravenous Revatio use and since pharmacokinetic models predict that 20 mg oral and 10 mg intravenous formulations will yield similar plasma exposures, the safety information for intravenous Revatio is supported by that of oral Revatio.
A 10 mg dose of Revatio solution for injection is predicted to provide total exposure of free sildenafil and its N-desmethyl metabolite and their combined pharmacological effects comparable to those of a 20 mg oral dose.
Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability and pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus injection to patients with Pulmonary Arterial Hypertension (PAH) who were already receiving and stable on oral Revatio 20 mg three times per day.
A total of 10 PAH subjects enrolled and completed the study. The mean postural changes in systolic and diastolic blood pressure over time were small (<10 mmHg) and returned towards baseline beyond 2 hours. No symptoms of hypotension were associated with these changes. The mean changes in heart rate were clinically insignificant. Two subjects experienced a total of 3 adverse reactions (flushing, flatulence and hot flush). There was one serious adverse reaction in a subject with severe ischaemic cardiomyopathy who experienced ventricular fibrillation and death 6 days post study. It was judged to be unrelated to the study medicinal product.
In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were randomized to and treated with 20 mg, 40 mg or 80 mg TID doses of oral Revatio and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID was 2.9%, 3.0% and 8.5% respectively, compared to 2.9% with placebo. Of the 277 subjects treated in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day (4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87% of 183 patients on study treatment were receiving Revatio 80 mg TID.
In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with oral Revatio (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2% compared to 10.7% in the placebo/epoprostenol treated patients. Newly reported adverse drug reactions, which occurred more frequently in the sildenafil/epoprostenol group, were ocular hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known adverse events headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68% of 133 patients on study treatment were receiving Revatio 80 mg TID.
In the two-placebo controlled oral Revatio studies adverse events were generally mild to moderate in severity. The most commonly reported adverse reactions that occurred (greater or equal to 10%) on Revatio compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.
Adverse reactions which occurred in >1% of Revatio-treated patients and were more frequent (>1% difference) on Revatio in the pivotal study or in the Revatio combined data set of both the placebo-controlled studies in pulmonary arterial hypertension, at oral doses of 20, 40 or 80 mg TID are listed in the table below by class and frequency grouping (very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to ≤1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Reports from post-marketing experience are included in italics.
Common: cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis
Common: anaemia
Common: fluid retention
Common: insomnia, anxiety
Very common: headache
Common: migraine, tremor, paraesthesia, burning sensation, hypoaesthesia
Common: retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia
Uncommon: visual acuity reduced, diplopia, abnormal sensation in eye
Not known: Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal vascular occlusion, Visual field defect*
Common: vertigo
Not known: sudden hearing loss
Very common: flushing
Not Known: hypotension
Common: epistaxis, cough, nasal congestion
Very common: diarrhoea, dyspepsia
Common: gastritis, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth
Common: alopecia, erythema, night sweats
Not known: rash
Very common: pain in extremity
Common: myalgia, back pain
Uncommon: haematuria
Uncommon: penile haemorrhage, haematospermia, gynaecomastia
Not known: priapism, erection increased
Common: pyrexia
* These adverse events/reactions have been reported in patients taking sildenafil in the treatment of male erectile dysfunction (MED).
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.
This medicinal product must not be mixed with other medicinal products or intravenous diluents except those mentioned in section 6.6.
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