ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Revatio 20 mg film-coated tablets
Each film-coated tablet contains 20 mg of sildenafil (as citrate). Revatio tablets also contain lactose.
For a full list of excipients, see section 6.1.
Film-coated tablet.
White, round, biconvex film-coated tablets marked “PFIZER” on one side and “RVT 20”on the other.
Treatment of 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.
Revatio is intended for oral use.
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.
Use in adults
The recommended dose is 20 mg three times a day. Tablets should be taken approximately 6 to
8 hours apart with or without food.
Use in the elderly
Dosage adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute
walk distance could be less in elderly patients.
Use in patients with renal impairment
Initial dose adjustments are not required in patients with renal impairment, including severe renal
impairment (creatinine clearance < 30 ml/min
).
A downward dose adjustment to 20 mg twice daily
should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.
Use in patients with hepatic impairment
Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and
B). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-
risk assessment only if therapy is not well-tolerated.
Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C), (see
section 4.3).
2
Use in children and adolescents
Revatio 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 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.
Use in patients using other medicines:
In general, any dose adjustment should be administered only after a careful benefit-risk assessment.
A downward dose adjustment to 20 mg twice daily should be considered when sildenafil is
co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A
downward dose adjustment to 20 mg once daily is recommended in case of co-administration with
more potent CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone. Dose adjustments
of sildenafil may be required when co-administered with CYP3A4 inducers (see section 4.5).
Hypersensitivity to the active substance or to any of the excipients.
Co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form due to the
hypotensive effects of nitrates see section 5.1).
Combination with the most potent of the CYP3A4 inhibitors (eg, ketoconazole, itraconazole,
ritonavir) (see section 4.5).
Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic
neuropathy (NAION), regardless of whether this episode was in connection or not with previous
PDE5 inhibitor exposure (see section 4.4).
The safety of sildenafil has not been studied in the following sub-groups of patients and its use is
therefore contraindicated:
Severe hepatic impairment,
Recent history of stroke or myocardial infarction,
Severe hypotension (blood pressure < 90/50 mmHg) at initiation.
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 with class I functional
classification of pulmonary arterial hypertension. No studies have been performed in related forms of
pulmonary arterial hypertension other than related to connective tissue disease and surgical repair.
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
3
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).
Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy have been reported in
connection with the intake of sildenafil and other PDE5 inhibitors. The patient should be advised that
in case of sudden visual defect, he should stop taking Revatio and consult a physician immediately
(see section 4.3).
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 minimize 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.
Lactose monohydrate is present in the tablet film coat. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
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:
4
Co-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections 4.8
and 5.1).
The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial
hypertension (eg, bosentan, iloprost) has not been studied in controlled clinical trials. Therefore,
caution is recommended in case of co-administration. There is a pharmacokinetic interaction between
sildenafil and bosentan (see below information on the interaction with CYP3A4 inducers and effects
of sildenafil on other medicinal products).
The safety and efficacy of Revatio when co-administered with other PDE5 inhibitors has not been
studied in pulmonary arterial hypertension patients.
Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a
reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with
CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the
only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with
pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and
CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients
not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg
three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration
range covers the increase in sildenafil exposure observed in specifically designed drug interaction
studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg,
ketoconazole, itraconazole, ritonavir).
CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in
pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with
CYP3A4 inducer bosentan.
Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19)
125 mg twice daily with sildenafil 80 mg three times a day (at steady state) concomitantly
administered during 6 days in healthy volunteers resulted in a 63% decrease of sildenafil AUC.
Caution is recommended in case of co-administration.
Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4
inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine.
Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at
steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300 % (4-fold)
increase in sildenafil C
max
and a 1,000 % (11-fold) increase in sildenafil plasma AUC. At 24 hours, the
plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml
when sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broad
range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with
ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state
(1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140 % increase in
sildenafil C
max
and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir
pharmacokinetics. For dose recommendations see section 4.2.
When a single 100 mg dose of sildenafil was administered with erythromycin, a specific CYP3A4
inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in sildenafil
systemic exposure (AUC). For dose recommendations see section 4.2. In normal healthy male
volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC,
C
max
, T
max
, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating
metabolite. No dose adjustment is required. Cimetidine (800 mg), a cytochrome P450 inhibitor and a
5
non-specific CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil concentrations when co-
administered with sildenafil (50 mg) to healthy volunteers. No dose adjustment is required.
The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected
to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin,
telithromycin and nefazodone are expected to have an effect in between that of ritonavir and CYP3A4
inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. Therefore
dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).
The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that
co-administration of beta-blockers in combination with CYP3A4 substrates might result in an
additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.
Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest
increases in plasma levels of sildenafil. No dose adjustment is required.
Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the
bioavailability of sildenafil.
Co-administration of oral contraceptives (ethinyloestradiol 30 g and levonorgestrel 150 g) did not
affect the pharmacokinetics of sildenafil.
Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has
the potential to have serious interaction with sildenafil (see section 4.3).
Effects of sildenafil on other medicinal products
In vitro studies:
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4
(IC
50
> 150 M).
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such
as theophylline or dipyridamole.
In vivo studies:
No significant interactions were shown when sildenafil (50 mg) was co-administered with
tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.
Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11%), suggesting that
sildenafil does not have a clinically relevant effect on CYP3A4.
No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid
(150 mg).
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). Caution is recommended in case of co-
administration.
In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in
hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg.
The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These
6
additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was
administered alone to healthy volunteers.
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and
sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign
prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean
additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and
8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg,
11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were
administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports
of patients who experienced symptomatic postural hypotension. These reports included dizziness and
lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-
blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 4.4).
Sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease
inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.
Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was
shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide
donors or nitrates in any form is therefore contraindicated (see section 4.3).
Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives
(ethinyloestradiol 30 g and levonorgestrel 150 g).
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 breast-
feeding mothers.
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 operating machinery. No studies on
the effects on the ability to drive and use machines have been performed.
In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207
patients were treated with Revatio at daily doses ranging from 20 mg to 80 mg three times a day and
70 patients were treated with placebo. The duration of treatment was 12 weeks. 259 subjects who
completed the pivotal study entered a long-term extension study. Doses up to 80 mg three times a day
(4 times the recommended dose of 20 mg three times a day) were studied (N = 149 patients treated for
at least 1 year, 101 on 80 mg three times a day). The overall frequency of discontinuation in sildenafil
treated patients at the recommended daily dose of 20 mg three times a day (2.9 %) was low and the
same as placebo (2.9 %).
In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary
arterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting
from 20 mg, to 40 mg and then 80 mg, three times a day) and epoprostenol, and 131 patients were
treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall
frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was
7
5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse drug
reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were bloodshot
eyes/red eyes, blurred vision, nasal congestion, night sweats, back pain and dry mouth. The known
adverse events headache, flushing, pain in extremity and oedema were noted in a higher frequency in
sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients.
In the two-placebo controlled studies adverse events were generally mild to moderate in severity. The
most commonly reported adverse reactions that occurred (greater or equal to 10 %) on Revatio
compared to placebo were headache, flushing, dyspepsia, diarrhoea and limb pain.
Adverse reactions which occurred in > 1 % of Revatio-treated patients and were more frequent (> 1 %
difference) on Revatio in the pivotal study or in the Revatio combined data set of both the placebo-
controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg three times a day
are listed in the table below by class and frequency grouping (very common ( 1/10), common
( 1/100 to < 1/10), uncommon ( 1/1000 to < 1/100) and not known (cannot be estimated from the
available data). Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Reports from post-marketing experience are included in italics.
MedDRA System Organ Class
Adverse Drug Reaction
Infections and infestations
Common
Cellulitis, influenza, sinusitis not
otherwise specified (NOS)
Blood and the lymphatic system disorders
Common
Anaemia NOS
Metabolism and nutrition disorders
Common
Fluid retention
Psychiatric disorders
Common
Insomnia, anxiety
Nervous system disorders
Very Common
Headache
Common
Migraine NOS, tremor, paraesthesia,
burning sensation NOS, hypoaesthesia
Eye disorders
Common
Retinal haemorrhage, visual
disturbance NOS, blurred vision,
photophobia, chromatopsia, cyanopsia,
eye irritation, blood shot eyes/red eyes
Uncommon
Visual acuity reduced, diplopia,
abnormal sensation in eye
Ear and labyrinth disorders
Common
Vertigo
Not known
Sudden deafness*
Vascular disorders
Very Common
Flushing
Not Known
Hypotension
8
Respiratory, thoracic and mediastinal disorders
Common
Bronchitis NOS, epistaxis, rhinitis
NOS, cough, nasal congestion
Gastrointestinal disorders
Very Common
Diarrhoea, dyspepsia
Common
Gastritis NOS, gastroenteritis NOS,
gastrooesophageal reflux disease,
haemorrhoids, abdominal distension,
dry mouth
Skin and subcutaneous tissue disorders
Common
Not known
Alopecia, erythema, night sweats
Skin rash
Musculoskeletal, connective tissue and bone
disorders
Very Common
Limb pain
Common
Myalgia, back pain
Reproductive system and breast disorders
Uncommon
Not known
Gynaecomastia
Priapism, prolonged erection
General disorders and administration site
conditions
Common
Pyrexia
* Sudden decrease or loss of hearing has been reported in a small number of post-marketing and
clinical trial cases with the use of all PDE5 inhibitors, including sildenafil.
In post marketing surveillance, adverse events/reactions that have been reported with an unknown
frequency in patients taking sildenafil in the treatment of male erectile dysfunction (MED) include:
Eye disorders: Non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vascular occlusion,
visual field defect.
In single dose volunteer studies of 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in erectile dysfunction, ATC code: G04BE03
9
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.
Studies
in vitro
have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5
than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved
in the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over
700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold
selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the
control of cardiac contractility.
Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of
cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients
with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure
was a decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a
day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were
observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose
of 20 mg three times a day no reductions in systolic or diastolic pressure were seen.
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant
effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial
hypertension no clinically relevant effects on the ECG were reported.
In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with
severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean
resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to
baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on
cardiac output, and did not impair blood flow through the stenosed coronary arteries.
Mild and transient differences in colour discrimination (blue/green) were detected in some subjects
using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident
after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related
to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has
no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients
with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg)
demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour
discrimination simulated traffic light, Humphrey perimeter and photostress).
Efficacy in adult patients with pulmonary arterial hypertension (PAH)
A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary
pulmonary hypertension, PAH associated with connective tissue disease (CTD), and PAH following
surgical repair of congenital heart lesions. Patients were randomised to one of four treatment groups:
placebo, sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients
randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 68
(25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline
6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients
(63%) included were diagnosed with primary pulmonary hypertension, 84 (30%) were diagnosed with
PAH associated with connective tissue disease (CTD) and 18 (7%) of the patients were diagnosed
with PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional
Class II (107/277, 39%) or III (160/277, 58%) with a mean baseline 6 minute walking distance of 378
meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4%) or IV (9/277, 3%) at
10
baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening fraction
< 0.2 were not studied.
Sildenafil (or placebo) was added to patients’ background therapy which could have included a
combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of
prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on
therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy
were excluded from the study.
The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance. A
statistically significant increase in 6-minute walk distance was observed in all 3 sildenafil dose groups
compared to those on placebo. Placebo corrected increases in walk distance were 45 metres
(p < 0.0001), 46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and
80 mg respectively. There was no significant difference in effect between sildenafil doses.
When analysed by WHO functional class, a statistically significant increase in 6-minute walk distance
was observed in the 20 mg dose group. For class II and class III, placebo corrected increases of 49
metres (p = 0.0007) and 45 metres (p = 0.0031) were observed respectively.
The improvement in walk distance was apparent after 4 weeks of treatment and this effect was
maintained at weeks 8 and 12. Results were generally consistent in subgroups according to baseline
walking distance, aetiology (primary and CTD-associated PAH), WHO functional class, gender, race,
location, mean PAP and PVRI.
Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary
arterial pressure (mPAP) compared to those on placebo. The placebo-corrected treatment was –
2.7 mmHg (p = 0.04) for sildenafil 20 mg three times a day. There was no evidence of a difference in
effect between sildenafil 20 mg and the higher doses tested. The mean change from baseline in
pulmonary vascular resistance (PVR) was –122 dyne.sec/cm
5
for sildenafil 20 mg three times a day.
The percent reduction at 12 weeks for sildenafil 20 mg in PVR (11.2%) was proportionally greater
than the reduction in systemic vascular resistance (SVR) (7.2%). The effect of sildenafil on mortality
is unknown.
Long-term Survival Data
Patients enrolled into the pivotal study were eligible to enter a long term open label extension study.
A total of 207 patients were treated with Revatio in the pivotal study, and their long term survival
status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and
3 year survival were 96%, 91% and 82%, respectively. Survival in patients of WHO functional class
II at baseline at 1, 2 and 3 years was 99%, 91%, and 84% respectively, and for patients of WHO
functional class III at baseline was 94%, 90%, and 81%, respectively.
Efficacy in adult patients with PAH (when used in combination with epoprostenol)
A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who
were stabilised on intravenous epoprostenol. The PAH patients included those with Primary
Pulmonary Arterial Hypertension (212/267, 79%) and PAH associated with CTD (55/267, 21%).
Most patients were WHO Functional Class II (68/267, 26%) or III (175/267, 66%); fewer patients
were Class I (3/267, 1%) or IV (16/267, 6%) at baseline; for a few patients (5/267, 2%), the WHO
Functional Class was unknown. Patients were randomised to placebo or sildenafil (in a fixed titration
starting from 20 mg, to 40 mg and then 80 mg, three times a day) when used in combination with
intravenous epoprostenol.
The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance.
There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk
distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of
sildenafil (95% CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance ≥ 325
metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline
11
walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients
with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with
PAH associated with CTD. The difference in results between these randomisation subgroups may
have arisen by chance in view of their limited sample size.
Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial
Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of
-3.9 mmHg was observed in favour of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical
worsening was a secondary endpoint as defined as the time from randomisation to the first occurrence
of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical
deterioration requiring a change in epoprostenol therapy). Treatment with sildenafil significantly
delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects
experienced clinical worsening events in the placebo group (17.6%) compared with 8 subjects in the
sildenafil group (6.0%).
5.2 Pharmacokinetic properties
Absorption:
Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to
120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral
bioavailability is 41 % (range 25-63 %). After oral three times a day dosing of sildenafil, AUC and
C
max
increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg
three times a day a more than dose proportional increase in sildenafil plasma levels has been
observed. In pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg
three times a day was on average 43 % (90 % CI: 27% - 60%) higher compared to the lower doses.
When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in T
max
of 60
minutes and a mean reduction in C
max
of 29 % however, the extent of absorption was not significantly
affected (AUC decreased by 11%).
Distribution:
The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into
the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma
concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major
circulating N-desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein
binding is independent of total drug concentrations.
Metabolism:
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic
microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil.
This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an
in vitro
potency
for PDE5 approximately 50 % that of the parent drug. The N-desmethyl metabolite is further
metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial
hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those of
sildenafil after 20 mg three times a day dosing (translating into a 36 % contribution to sildenafil’s
pharmacological effects). The subsequent effect on efficacy is unknown.
Elimination:
The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3-5 h. After
either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the
faeces (approximately 80 % of administered oral dose) and to a lesser extent in the urine
(approximately 13 % of administered oral dose).
Pharmacokinetics in special patient groups
Elderly:
12
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in
approximately 90 % higher plasma concentrations of sildenafil and the active N-desmethyl metabolite
compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma
protein binding, the corresponding increase in free sildenafil plasma concentration was approximately
40 %.
Renal insufficiency:
In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml/min), the
pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. In volunteers
with severe renal impairment (creatinine clearance < 30 ml/min), sildenafil clearance was reduced,
resulting in mean increases in AUC and C
max
of 100 % and 88 % respectively compared to age-
matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C
max
values were significantly increased 200 % and 79 % respectively in subjects with severe renal
impairment compared to subjects with normal renal function.
Hepatic insufficiency:
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) sildenafil clearance
was reduced, resulting in increases in AUC (85 %) and C
max
(47 %) compared to age-matched
volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and C
max
values
were significantly increased by 154 % and 87 %, respectively in cirrhotic subjects compared to
subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely
impaired hepatic function have not been studied.
Population pharmacokinetics:
In patients with pulmonary arterial hypertension, the average steady state concentrations were
20 - 50 % higher over the investigated dose range of 20–80 mg three times a day compared to healthy
volunteers. There was a doubling of the C
min
compared to healthy volunteers. Both findings suggest a
lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterial
hypertension compared to healthy volunteers.
5.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, fertility and
embryonal/foetal development.
In pups of rats which were pre- and postnatally treated with 60 mg/kg sildenafil, a decreased litter
size, a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were
approximately fifty times the expected human exposure at 20 mg three times a day. These effects
were observed at exposures considered sufficiently in excess of the maximum human exposure
indicating little relevance to clinical use.
6.1 List of excipients
Tablet core:
microcrystalline cellulose
calcium hydrogen phosphate (anhydrous)
croscarmellose sodium
magnesium stearate
13
Film coat:
hypromellose
titanium dioxide (E171)
lactose monohydrate
glycerol triacetate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
Do not store above 30 °C. Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/Aluminium blisters of 90 tablets (15 tablets per blister strip) in a carton.
6.6 Special precautions for disposal
No special requirements.
Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom.
EU/1/05/318/001
Date of first authorisation: 28 October 2005
Date of latest renewal: 23 September 2010
Detailed information on this product is available on the website of the European Medicines Agency
14
Revatio 0.8 mg/ml solution for injection
Each ml of solution contains 0.8 mg of sildenafil (as citrate). Each 20 ml vial contains 12.5 ml of
solution (10 mg of sildenafil,as citrate).
For a full list of excipients, see section 6.1.
Solution for injection.
Clear, colourless solution.
Revatio solution for injection is for the treatment of patients with pulmonary arterial hypertension
who are currently prescribed oral Revatio and who are temporarily unable to take oral medicine, but
are otherwise clinically and haemodynamically stable.
Revatio (oral) is indicated for treatment of patients with pulmonary arterial hypertension classified as
WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary
pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.
Treatment should only be initiated and monitored by a physician experienced in the treatment of
pulmonary arterial hypertension. In case of clinical deterioration in spite of Revatio treatment,
alternative therapies should be considered.
Revatio solution for injection should be administered to patients already prescribed oral Revatio as a
replacement for oral administration under conditions where they are temporarily unable to take oral
Revatio therapy.
Revatio solution for injection is for intravenous use as a bolus injection.
Use in adults
The recommended dose is 10 mg (corresponding to 12.5 ml) three times a day administered as an
intravenous bolus injection (see section 6.6).
A 10 mg dose of Revatio solution for injection is predicted to provide exposure of sildenafil and its
N-desmethyl metabolite and pharmacological effects comparable to those of a 20 mg oral dose.
Use in the elderly
Dosage adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute
walk distance could be less in elderly patients.
Use in patients with renal impairment
15
Initial dose adjustments are not required in patients with renal impairment, including severe renal
impairment (creatinine clearance < 30 ml/min
).
A downward dose adjustment to 10 mg twice daily
should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.
Use in patients with hepatic impairment
Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A
and B). A downward dose adjustment to 10 mg twice daily should be considered after a careful
benefit-risk assessment only if therapy is not well-tolerated.
Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C), (see
section 4.3).
Use in children and adolescents
Revatio 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.
Use in patients using other medicines:
In general, any dose adjustment should be administered only after a careful benefit-risk assessment.
A downward dose adjustment to 10 mg twice daily should be considered when sildenafil is
co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A
downward dose adjustment to 10 mg once daily is recommended in case of co-administration with
more potent CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone. Dose adjustments
of sildenafil may be required when co-administered with CYP3A4 inducers (see section 4.5).
Hypersensitivity to the active substance or to any of the excipients.
Co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form due to the
hypotensive effects of nitrates (see section 5.1).
Combination with the most potent of the CYP3A4 inhibitors (eg, ketoconazole, itraconazole,
ritonavir) (see section 4.5).
Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic
neuropathy (NAION), regardless of whether this episode was in connection or not with previous
PDE5 inhibitor exposure (see section 4.4).
The safety of sildenafil has not been studied in the following sub-groups of patients, and its use is
therefore contraindicated:
Severe hepatic impairment,
Recent history of stroke or myocardial infarction,
Severe hypotension (blood pressure < 90/50 mmHg) at initiation.
No clinical data is available for sildenafil IV administration in patients who are clinically or
haemodynamically unstable. Its use is accordingly not recommended in these patients.
16
When prescribing sildenafil, physicians should carefully consider whether patients with certain
underlying conditions could be adversely affected by sildenafil’s mild to moderate vasodilatory
effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular
outflow obstruction or autonomic dysfunction (see section 4.4).
The efficacy of Revatio has not been established in patients with severe pulmonary arterial
hypertension (functional class IV). If the clinical situation deteriorates, therapies that are
recommended at the severe stage of the disease (eg, epoprostenol) should be considered (see
section 4.2).
The benefit-risk balance of sildenafil has not been established in patients with class I functional
classification of pulmonary arterial hypertension. No studies have been performed in related forms of
pulmonary arterial hypertension other than related to connective tissue disease and surgical repair.
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.
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).
Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy have been reported in
connection with the intake of sildenafil and other PDE5 inhibitors. The patient should be advised that
in case of sudden visual defect, he should stop taking Revatio and consult a physician immediately
(see section 4.3).
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 minimize 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.
17
Unless otherwise specified, drug interaction studies have been performed in healthy adult male
subjects using oral sildenafil. These results are relevant to other populations and routes of
administration.
Effects of other medicinal products on intravenous sildenafil
Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4
inhibitors should be less than observed after oral sildenafil administration. The magnitude of the
interaction is expected to be reduced for intravenous sildenafil, as interactions for oral sildenafil are
due, at least in part, to effects on oral first pass metabolism.
Effects of other medicinal products on oral sildenafil
In vitro studies:
Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major
route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil
clearance and inducers of these isoenzymes may increase sildenafil clearance. For dose
recommendations see sections 4.2 and 4.3.
In vivo studies:
Co-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections 4.8
and 5.1).
The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial
hypertension (eg, bosentan, iloprost) has not been studied in controlled clinical trials. Therefore,
caution is recommended in case of co-administration. There is a pharmacokinetic interaction between
sildenafil and bosentan (see below information on the interaction with CYP3A4 inducers and effects
of sildenafil on other medicinal products).
The safety and efficacy of Revatio when co-administered with other PDE5 inhibitors has not been
studied in pulmonary arterial hypertension patients.
Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a
reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with
CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the
only factors with a statistically significant impact on oral sildenafil pharmacokinetics in patients with
pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and
CYP3A4 substrates plus beta-blockers was 43% and 66% higher, respectively, compared to patients
not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at an oral dose of
80 mg three times a day compared to the exposure at an oral dose of 20 mg three times a day. This
concentration range covers the increase in sildenafil exposure observed in specifically designed drug
interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg,
ketoconazole, itraconazole, ritonavir).
CYP3A4 inducers seemed to have a substantial impact on the oral pharmacokinetics of sildenafil in
pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with
CYP3A4 inducer bosentan. Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9
and possibly of CYP2C19) 125 mg twice daily with oral sildenafil 80 mg three times a day (at steady
state) concomitantly administered during 6 days in healthy volunteers resulted in a 63% decrease of
sildenafil AUC. Caution is recommended in case of co-administration.
Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4
inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine.
18
Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at
steady state (500 mg twice daily) with oral sildenafil (100 mg single dose) resulted in a 300% (4-fold)
increase in sildenafil C
max
and a 1,000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the
plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml
when sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broad
range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with
ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state
(1200 mg three times a day) with oral sildenafil (100 mg single dose) resulted in a 140% increase in
sildenafil C
max
and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir
pharmacokinetics. For dose recommendations see sections 4.2.
When a single 100 mg dose of oral sildenafil was administered with erythromycin, a specific CYP3A4
inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil
systemic exposure (AUC). For dose recommendations see sections 4.2. In normal healthy male
volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC,
C
max
, T
max
, elimination rate constant, or subsequent half-life of oral sildenafil or its principal
circulating metabolite. No dose adjustment is required. Cimetidine (800 mg), a cytochrome P450
inhibitor and a non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil
concentrations when co-administered with oral sildenafil (50 mg) to healthy volunteers. No dose
adjustment is required.
The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected
to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin,
telithromycin and nefazodone) are expected to have an effect in between that of ritonavir and
CYP3A4 inhibitors like saquinavir or erythromycin), a seven-fold increase in exposure is assumed.
Therefore dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).
The population pharmacokinetic analysis in pulmonary arterial hypertension patients receiving oral
sildenafil suggested that co-administration of beta-blockers in combination with CYP3A4 substrates
might result in an additional increase in sildenafil exposure compared with administration of CYP3A4
substrates alone.
Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest
increases in plasma levels of oral sildenafil. No dose adjustment is required.
Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the oral
bioavailability of sildenafil.
Co-administration of oral contraceptives (ethinyloestradiol 30 g and levonorgestrel 150 g) did not
affect the oral pharmacokinetics of sildenafil.
Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has
the potential to have serious interaction with sildenafil (see section 4.3).
Effects of oral sildenafil on other medicinal products
In vitro studies:
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4
(IC
50
> 150 M).
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such
as theophylline or dipyridamole.
In vivo studies:
19
No significant interactions were shown when oral sildenafil (50 mg) was co-administered with
tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.
Oral sildenafil had no significant effect on atorvastatin exposure (AUC increased 11%), suggesting
that sildenafil does not have a clinically relevant effect on CYP3A4.
No interactions were observed between sildenafil (100 mg single oral dose) and acenocoumarol.
Oral sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid
(150 mg).
Oral sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with
mean maximum blood alcohol levels of 80 mg/dl.
In a study of healthy volunteers oral sildenafil at steady state (80 mg three times a day) resulted in a
50% increase in bosentan AUC (125 mg twice daily). Caution is recommended in case of co-
administration.
In a specific interaction study, where oral sildenafil (100 mg) was co-administered with amlodipine in
hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg.
The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These
additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was
administered alone to healthy volunteers.
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and oral
sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign
prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean
additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and
8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg,
11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were
administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports
of patients who experienced symptomatic postural hypotension. These reports included dizziness and
lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-
blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 4.4).
Sildenafil (100 mg single oral dose) did not affect the steady state pharmacokinetics of the HIV
protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.
Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was
shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide
donors or nitrates in any form is therefore contraindicated (see section 4.3).
Oral sildenafil had no clinically significant impact on the plasma levels of oral contraceptives
(ethinyloestradiol 30 g and levonorgestrel 150 g).
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 breast-
feeding mothers.
20
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 operating machinery. No studies on
the effects on the ability to drive and use machines have been performed.
oral Revatio use. Since there are limited data for intravenous Revatio use and since pharmacokinetic
models predict that 20 mg oral and 10 mg intravenous formulations will yield similar plasma
exposures, the safety information for intravenous Revatio is supported by that of oral Revatio.
Intravenous administration
A 10 mg dose of Revatio solution for injection is predicted to provide total exposure of free sildenafil
and its N-desmethyl metabolite and their combined pharmacological effects comparable to those of a
20 mg oral dose.
Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability
and pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus
injection to patients with Pulmonary Arterial Hypertension (PAH) who were already receiving and
stable on oral Revatio 20 mg TID.
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 event in a subject with severe ischaemic
cardiomyopathy who experienced ventricular fibrillation and death 6 days post study drug; it was
judged to be unrelated to study drug.
Oral administration
In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of
207 patients were treated with oral Revatio at daily doses ranging from 20 mg to 80 mg three times a
day and 70 patients were treated with placebo. The duration of treatment was 12 weeks. 259 subjects
who completed the pivotal study entered a long-term extension study. Doses up to 80 mg three times a
day (4 times the recommended dose of 20 mg three times a day) were studied (N = 149 patients
treated for at least 1 year, 101 on 80 mg three times a day). The overall frequency of discontinuation
in sildenafil treated patients at the recommended daily dose of 20 mg three times a day (2.9%) was
low and the same as placebo (2.9%).
In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary
arterial hypertension, a total of 134 patients were treated with oral Revatio (in a fixed titration starting
from 20 mg, to 40 mg and then 80 mg, three times a day) and epoprostenol, and 131 patients were
treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall
frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was
5.2% compared to 10.7% in the placebo/epoprostenol treated patients. Newly reported adverse drug
reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were bloodshot
eyes/red eyes, blurred vision, nasal congestion, night sweats, back pain and dry mouth. The known
adverse events headache, flushing, pain in extremity and oedema were noted in a higher frequency in
sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients.
In the two-placebo controlled oral Revatio studies adverse events were generally mild to moderate in
severity. The most commonly reported adverse reactions that occurred (greater or equal to 10%) on
Revatio compared to placebo were headache, flushing, dyspepsia, diarrhoea and limb pain.
21
Adverse reactions which occurred in > 1% of Revatio-treated patients and were more frequent (> 1%
difference) on Revatio in the pivotal study or in the Revatio combined data set of both the placebo-
controlled studies in pulmonary arterial hypertension, at oral doses of 20, 40 or 80 mg three times a
day are listed in the table below by class and frequency grouping (very common ( 1/10), common
( 1/100 to < 1/10), uncommon ( 1/1000 to ≤ 1/100) and not known (cannot be estimated from the
available data). Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Reports from post-marketing experience are included in italics.
MedDRA System Organ Class
Adverse Drug Reaction
Infections and infestations
Common
Cellulitis, influenza, sinusitis not
otherwise specified (NOS)
Blood and the lymphatic system disorders
Common
Anaemia NOS
Metabolism and nutrition disorders
Common
Fluid retention
Psychiatric disorders
Common
Insomnia, anxiety
Nervous system disorders
Very Common
Headache
Common
Migraine NOS, tremor, paraesthesia,
burning sensation NOS, hypoaesthesia
Eye disorders
Common
Retinal haemorrhage, visual
disturbance NOS, blurred vision,
photophobia, chromatopsia, cyanopsia,
eye irritation, blood shot eyes/red eyes
Uncommon
Visual acuity reduced, diplopia,
abnormal sensation in eye
Ear and labyrinth disorders
Common
Vertigo
Not known
Sudden deafness*
Vascular disorders
Very Common
Flushing
Not Known
Hypotension
Respiratory, thoracic and mediastinal disorders
Common
Bronchitis NOS, epistaxis, rhinitis
NOS, cough, nasal congestion
Gastrointestinal disorders
Very Common
Diarrhoea, dyspepsia
Common
Gastritis NOS, gastroenteritis NOS,
gastrooesophageal reflux disease,
haemorrhoids, abdominal distension,
22
dry mouth
Skin and subcutaneous tissue disorders
Common
Not known
Alopecia, erythema, night sweats
Skin rash
Musculoskeletal, connective tissue and bone
disorders
Very Common
Limb pain
Common
Myalgia, back pain
Reproductive system and breast disorders
Uncommon
Not known
Gynaecomastia
Priapism, prolonged erection
General disorders and administration site
conditions
Common
Pyrexia
* Sudden decrease or loss of hearing has been reported in a small number of post-marketing and
clinical trial cases with the use of all PDE5 inhibitors, including sildenafil.
In post marketing surveillance, adverse events/reactions that have been reported with an unknown
frequency in patients taking sildenafil in the treatment of male erectile dysfunction (MED) include:
Eye disorders: Non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vascular occlusion,
visual field defect.
In single dose volunteer studies of oral doses up to 800 mg, adverse reactions were similar to those
seen at lower doses, but the incidence rates and severities were increased. At single oral doses of
200 mg the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion,
and altered vision) was increased.
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is
not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not
eliminated in the urine.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in erectile dysfunction, ATC code: G04BE03
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.
23
Studies
in vitro
have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5
than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved
in the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over
700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold
selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the
control of cardiac contractility.
Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of
cases, do not translate into clinical effects. After chronic oral dosing of 80 mg three times a day to
patients with systemic hypertension the mean change from baseline in systolic and diastolic blood
pressure was a decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic oral dosing of 80 mg
three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure
reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the
recommended oral dose of 20 mg three times a day no reductions in systolic or diastolic pressure were
seen.
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant
effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial
hypertension no clinically relevant effects on the ECG were reported.
In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with
severe coronary artery disease (CAD) (> 70% stenosis of at least one coronary artery), the mean
resting systolic and diastolic blood pressures decreased by 7% and 6% respectively compared to
baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on
cardiac output, and did not impair blood flow through the stenosed coronary arteries.
Mild and transient differences in colour discrimination (blue/green) were detected in some subjects
using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident
after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related
to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has
no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients
with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg)
demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour
discrimination simulated traffic light, Humphrey perimeter and photostress).
Efficacy of intravenous sildenafil in adult patients with pulmonary arterial hypertension (PAH)
A 10 mg dose of Revatio solution for injection is predicted to provide total exposure of free sildenafil
and its N-desmethyl metabolite and their combined pharmacological effects comparable to those of a
20 mg oral dose. This is based on Pharmacokinetic data only (see section 5.2. Pharmacokinetic
Properties). The consequences of the subsequent lower exposure to the active N-desmethyl
metabolite observed after repeated IV administration of Revatio have not been documented. No
clinical studies have been performed to demonstrate that these formulations have comparable efficacy
Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability
and pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus
injection to patients with PAH who were already receiving and stable on oral Revatio 20 mg TID.
A total of 10 PAH subjects enrolled and completed the study. Eight subjects were taking bosentan and
one subject was taking treprostinil in addition to bosentan and Revatio. After dosing, sitting and
standing blood pressure and heart rate were recorded at 30, 60, 120, 180 and 360 minute post dose.
The mean changes from baseline in sitting blood pressure were greatest at 1 hour, -9.1 mmHg
(SD ± 12.5) and -3.0 (SD ± 4.9) mmHg for systolic and diastolic pressure respectively. The mean
postural changes in systolic and diastolic blood pressure over time were small (< 10 mmHg) and
returned towards baseline beyond 2 hours.
24
Efficacy of oral sildenafil in adult patients with pulmonary arterial hypertension (PAH)
A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary
pulmonary hypertension, PAH associated with connective tissue disease (CTD), and PAH following
surgical repair of congenital heart lesions. Patients were randomised to one of four treatment groups:
placebo, sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients
randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 68
(25%) men and 209 (75%) women with a mean age of 49 years (range: 18-81 years) and baseline
6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients
(63%) included were diagnosed with primary pulmonary hypertension, 84 (30%) were diagnosed with
PAH associated with connective tissue disease (CTD) and 18 (7%) of the patients were diagnosed
with PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional
Class II (107/277, 39%) or III (160/277, 58%) with a mean baseline 6 minute walking distance of 378
meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4%) or IV (9/277, 3%) at
baseline. Patients with left ventricular ejection fraction < 45% or left ventricular shortening fraction
< 0.2 were not studied.
Sildenafil (or placebo) was added to patients’ background therapy which could have included a
combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of
prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on
therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy
were excluded from the study.
The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance. A
statistically significant increase in 6-minute walk distance was observed in all 3 sildenafil dose groups
compared to those on placebo. Placebo corrected increases in walk distance were 45 metres
(p < 0.0001), 46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and
80 mg respectively. There was no significant difference in effect between sildenafil doses.
When analysed by WHO functional class, a statistically significant increase in 6-minute walk distance
was observed in the 20 mg dose group. For class II and class III, placebo corrected increases of
49 metres (p = 0.0007) and 45 metres (p = 0.0031) were observed respectively.
The improvement in walk distance was apparent after 4 weeks of treatment and this effect was
maintained at weeks 8 and 12. Results were generally consistent in subgroups according to baseline
walking distance, aetiology (primary and CTD-associated PAH), WHO functional class, gender, race,
location, mean PAP and PVRI.
Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary
arterial pressure (mPAP) compared to those on placebo. The placebo-corrected treatment was
-2.7 mmHg (p = 0.04) for sildenafil 20 mg three times a day. There was no evidence of a difference in
effect between sildenafil 20 mg and the higher doses tested. The mean change from baseline in
pulmonary vascular resistance (PVR) was –122 dyne.sec/cm
5
for sildenafil 20 mg three times a day.
The percent reduction at 12 weeks for sildenafil 20 mg in PVR (11.2%) was proportionally greater
than the reduction in systemic vascular resistance (SVR) (7.2%). The effect of sildenafil on mortality
is unknown.
Long-term Survival Data
Patients enrolled into the pivotal oral route study were eligible to enter a long term open label
extension study. A total of 207 patients were treated with Revatio in the pivotal study, and their long
term survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier
estimates of 1, 2 and 3 year survival were 96%, 91% and 82%, respectively. Survival in patients of
WHO functional class II at baseline at 1, 2 and 3 years was 99%, 91%, and 84% respectively, and for
patients of WHO functional class III at baseline was 94%, 90%, and 81%, respectively.
25
Efficacy of oral sildenafil in adult patients with PAH (when used in combination with epoprostenol)
A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who
were stabilised on intravenous epoprostenol. The PAH patients included those with Primary
Pulmonary Arterial Hypertension (212/267, 79%) and PAH associated with CTD (55/267, 21%).
Most patients were WHO Functional Class II (68/267, 26%) or III (175/267, 66%); fewer patients
were Class I (3/267, 1%) or IV (16/267, 6%) at baseline; for a few patients (5/267, 2%), the WHO
Functional Class was unknown. Patients were randomised to placebo or sildenafil (in a fixed titration
starting from 20 mg, to 40 mg and then 80 mg, three times a day) when used in combination with
intravenous epoprostenol.
The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance.
There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk
distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of
sildenafil (95% CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance
≥ 325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline
walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients
with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with
PAH associated with CTD. The difference in results between these randomisation subgroups may
have arisen by chance in view of their limited sample size.
Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial
Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of
-3.9 mmHg was observed in favour of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical
worsening was a secondary endpoint as defined as the time from randomisation to the first occurrence
of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical
deterioration requiring a change in epoprostenol therapy). Treatment with sildenafil significantly
delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects
experienced clinical worsening events in the placebo group (17.6%) compared with 8 subjects in the
sildenafil group (6.0%).
5.2 Pharmacokinetic properties
Absorption:
The mean absolute oral bioavailability for sildenafil is 41% (range 25-63%). In study A1481262 C
max
,
CL and AUC (0-8) of 248 ng/ml, 30.3 L/h and 330 ng h/ml, were observed respectively. The C
max
and
AUC (0-8) of the N-desmethyl metabolite were 30.8 ng/ml and 147 ng h/ml, respectively.
Distribution:
The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into
the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma
concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major
circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding
is independent of total drug concentrations.
Metabolism:
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic
microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil.
This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an
in vitro
potency
for PDE5 approximately 50% that of the parent drug. The N-desmethyl metabolite is further
metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial
hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72% those of
sildenafil after 20 mg three times a day oral dosing (translating into a 36% contribution to sildenafil’s
pharmacological effects). The subsequent effect on efficacy is unknown. In healthy volunteers, the
plasma levels of the N-desmethyl metabolite following intravenous dosing are significantly lower than
those observed following oral dosing. At steady state plasma concentrations of N-desmethyl
26
metabolite are approximately 16% versus 61% those of sildenafil after IV and oral dosing,
respectively.
Elimination:
The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3-5 h. After
either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the
faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine
(approximately 13% of administered oral dose).
Pharmacokinetics in special patient groups
Elderly:
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in
approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite
compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma
protein binding, the corresponding increase in free sildenafil plasma concentration was approximately
40%.
Renal insufficiency:
In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml/min), the
pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. In volunteers
with severe renal impairment (creatinine clearance < 30 ml/min), sildenafil clearance was reduced,
resulting in mean increases in AUC and C
max
of 100% and 88% respectively compared to age-matched
volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C
max
values were
significantly increased 200% and 79% respectively in subjects with severe renal impairment
compared to subjects with normal renal function.
Hepatic insufficiency:
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) sildenafil clearance
was reduced, resulting in increases in AUC (85%) and C
max
(47%) compared to age-matched
volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and C
max
values
were significantly increased by 154% and 87%, respectively in cirrhotic subjects compared to
subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely
impaired hepatic function have not been studied.
Population pharmacokinetics:
In patients with pulmonary arterial hypertension, the average steady state concentrations were
20 - 50% higher over the investigated oral dose range of 20–80 mg three times a day compared to
healthy volunteers. There was a doubling of the C
min
compared to healthy volunteers. Both findings
suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary
arterial hypertension compared to healthy volunteers.
5.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, fertility and
embryonal/foetal development.
In pups of rats which were pre- and postnatally treated with 60 mg/kg sildenafil, a decreased litter
size, a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were
approximately fifty times the expected human intravenous exposure at 10 mg three times a day. These
effects were observed at exposures considered sufficiently in excess of the maximum human exposure
indicating little relevance to clinical use.
27
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
0.9% sodium chloride 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 product or waste material should be disposed of in accordance with local requirements.
Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom.
EU/1/05/318/002
28
Date of first authorisation: 28 October 2005
Date of latest renewal: 23 September 2010
Detailed information on this product is available on the website of the European Medicines Agency
29
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
30
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Pfizer PGM
Zone Industrielle
29 route des Industries
37530 Poce sur Cisse
FRANCE
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder (MAH) shall agree the details of a controlled distribution system
for the 20 ml vial of Revatio 0.8 mg/ml solution for injection with the National Competent Authorities
and must implement such programme nationally to ensure that prior to prescribing all health care
professionals who intend to prescribe and/or dispense Revatio 0.8 mg/ml solution for injection are
provided with the following:
- Information for Healthcare professionals
- Copy of the Summary of Product Characteristics (SPC)
- Data Capture Form (DCF) designed to facilitate reporting of events of hypotension and
associated problems
The Information for Healthcare professionals should contain the following key elements:
- Information about the Pharmacovigilance Monitoring Programme regarding the potential risk
of clinically relevant hypotension and related problems to be put into place with the use of the
DCF.
- Information on the switch from the 50 ml vial to the 20 ml vial for Revatio 0.8 mg/ml solution
The Marketing Authorisation Holder shall agree the Information for Healthcare professionals, and the
healthcare professionals to be targeted, with the national competent authority of each Member State
prior to the launch of the 20 ml vial of Revatio 0.8 mg/ml solution for injection in that country
.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 4.5 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
31
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
32
ANNEX III
LABELLING AND PACKAGE LEAFLET
33
A. LABELLING
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/CARTON
REVATIO 20 mg film-coated tablets
Sildenafil
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 20 mg of sildenafil (as citrate).
3. LIST OF EXCIPIENTS
Contains lactose monohydrate
See leaflet for further information
90 film-coated tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP:
9. SPECIAL STORAGE CONDITIONS
Do not store above 30
o
C. Store in the original package in order to protect from moisture.
35
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/05/318/001
13. BATCH NUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
REVATIO 20 mg
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
NATURE/TYPE: Vial carton and vial label
Revatio 0.8 mg/ml solution for injection
Sildenafil
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml of solution contains 0.8 mg of sildenafil (as citrate). Each 20 ml vial contains 12.5 ml
(10 mg sildenafil, as citrate)
3. LIST OF EXCIPIENTS
Contains glucose and water for injections
Solution for injection.
1 vial 10 mg/12.5 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
37
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/05/318/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Revatio 0.8 mg/ml
38
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
IMMEDIATE PACKAGING/BLISTER
REVATIO 20 mg
Sildenafil
Pfizer
3. EXPIRY DATE
EXP:
4. BATCH NUMBER
Batch:
5. OTHER
39
B. PACKAGE LEAFLET
40
PACKAGE LEAFLET: INFORMATION FOR THE USER
Revatio 20 mg film-coated tablets
Sildenafil
Read all of this leaflet carefully before you start taking this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, please ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What Revatio is and what it is used for
2. Before you take Revatio
3. How to take Revatio
4. Possible side effects
5 How to store Revatio
6. Further information
1. WHAT REVATIO IS AND WHAT IT IS USED FOR
Revatio belongs to a group of medicines called phosphodiesterase type 5 inhibitors.
Revatio brings down pulmonary blood pressure by widening the blood vessels in the lungs.
Revatio is used to treat pulmonary arterial hypertension (high blood pressure in the blood vessels in
the lungs).
2. BEFORE YOU TAKE REVATIO
Do not take Revatio
- If you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Revatio.
- If you are taking medicines containing nitrates, or nitric oxide donors such as amyl nitrate
(“poppers”). These medicines are often given for relief of angina pectoris (or “chest pain”).
Revatio can cause a serious increase in the effects of these medicines. Tell your doctor if you
are taking any of these medicines. If you are not certain, ask your doctor or pharmacist.
- If you have recently had a stroke, a heart attack or if you have severe liver disease or very low
blood pressure (<90/50 mmHg).
- If you are taking a medicine containing ketoconazole or itraconazole (to treat fungal infections)
or containing ritonavir (for HIV).
- If you have ever had loss of vision because of a problem with blood flow to the nerve in the eye
called non-arteritic anterior ischaemic optic neuropathy (NAION).
Take special care with Revatio
Tell your doctor
- If you have a severe heart problem.
- If you have
Retinitis pigmentosa
(a rare inherited eye disease).
- If you have sickle cell anaemia (an abnormality of red blood cells), leukaemia (cancer of blood
cells), multiple myeloma (cancer of bone marrow), or any disease or deformity of the penis.
41
- If you currently have a stomach ulcer, a bleeding disorder (such as haemophilia) or problems
with nose bleeds.
- If your disease is due to a blocked or narrow vein in the lungs rather than a blocked or narrow
artery.
- If you experience sudden decrease or loss of vision, stop taking Revatio and contact your
doctor immediately.
Special considerations for children and adolescents
Revatio should not be given to children and adolescents under the age of 18.
Special considerations for patients with kidney or liver problems
You should tell your doctor if you have kidney or liver problems, as your dose may need to be
adjusted.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
If you are taking other therapies for pulmonary hypertension (e.g. bosentan, iloprost) ask your doctor
or pharmacist for advice before taking Revatio.
If you are taking medicines containing St. John’s Wort (herbal medicinal product), rifampicin (used to
treat bacterial infections), carbamazepine, phenytoin and phenobarbital (used, among others, to treat
epilepsy) please inform your doctor or pharmacy before taking Revatio.
If you are taking medicines that inhibit blood clotting (for example warfarin) please inform your
doctor or pharmacist before taking Revatio.
If you are taking medicines containing erythromycin, clarithromycin, telithromycin (these are
antibiotics used to treat certain bacterial infections), saquinavir (for HIV) or nefazodone (for mental
depression), ask your doctor or pharmacist for advice before taking Revatio, as your dose may need to
be adjusted.
If you are taking alpha-blocker therapy for the treatment of high blood pressure or prostate problems,
ask your doctor or pharmacist for advice before taking Revatio.
Taking Revatio with food and drink
Revatio can be taken with or without food.
Pregnancy and breast feeding
If you are pregnant, or think you might be pregnant, ask your doctor or pharmacist for advice before
taking Revatio. Revatio should not be used during pregnancy unless strictly necessary.
Stop breast feeding when you start Revatio treatment. Revatio should not be given to women who are
breast feeding since it is not known if the medicine passes into the breast milk.
Driving and using machines
Revatio can cause dizziness and can affect vision. You should be aware of how you react to the
medicinal product before you drive or use machinery.
Important information about some of the ingredients of Revatio
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicinal product.
42
3. HOW TO TAKE REVATIO
Always take Revatio exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The recommended dose is 20 mg three times a day (taken 6 to 8 hours
apart) taken with or without food.
If you take more Revatio than you should
You should not take more tablets than your doctor tells you to.
If you take more tablets than you have been told to take contact your doctor.
If you forget to take Revatio
If you forget to take Revatio, take a dose as soon as you remember, then continue to take your tablets
at the usual times. Do not take a double dose to make up for a forgotten dose.
If you stop taking Revatio
Suddenly stopping your treatment with Revatio may lead to your symptoms getting worse. Do not
stop taking Revatio unless your doctor tells you to. Your doctor may tell you to reduce the dose over
a few days before stopping completely.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Revatio can cause side effects, although not everybody gets them.
In clinical trials side effects reported very commonly (seen in more than 1 in 10 patients) were
headache, facial flushing, indigestion, diarrhoea and limb pain.
Other side effects reported commonly (seen in less than 1 in 10 but more than 1 in 100 patients)
included: infection under the skin, flu-like symptoms, sinusitis, anaemia, fluid retention, difficulty
sleeping, anxiety, migraine, tremor, pins and needles, burning sensation, reduced skin sensation,
bleeding at the back of the eye, effects on vision, blurred vision and light sensitivity, effects on colour
vision, eye irritation, bloodshot eyes /red eyes, vertigo, bronchitis, nosebleed, runny nose, cough,
stuffy nose, stomach inflammation, gastroenteritis, heartburn, piles, abdominal distension, dry mouth,
hair loss, redness of the skin, night sweats, muscle aches, back pain and increased body temperature.
Other side effects reported less commonly (seen in less than 1 in 100 but more than 1 in 1000
patients) included: reduced sharpness of vision, double vision, abnormal sensation in the eye and
breast enlargement in men.
Skin rash has also been reported.
Sudden decrease or loss of hearing has been reported.
Decreased blood pressure has been reported.
Revatio contains the same active substance, sildenafil, that is used to treat men with male erectile
dysfunction (MED). Sildenafil belongs to a class of medicine called phosphodiesterase type 5 (PDE5)
inhibitors. When used to treat MED, the following visual side effects have been reported with PDE5
inhibitors, including sildenafil: partial, sudden, temporary, or permanent decrease or loss of vision in
one or both eyes.
Prolonged and sometimes painful erections have been reported after taking sildenafil. If you have
such an erection, which lasts continuously for more than 4 hours, you should contact a doctor
immediately.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist
43
5. HOW TO STORE REVATIO
Keep out of the reach and sight of children.
Do not use Revatio after the expiry date which is stated on the carton. The expiry date refers to the
last day of that month.
Do not store above 30
O
C. Store in the original package in order to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Revatio contains
- The active substance is sildenafil. Each tablet contains 20 mg of sildenafil (as the citrate).
- The other ingredients are:
Tablet core: microcrystalline cellulose, calcium hydrogen phosphate (anhydrous),
croscarmellose sodium, magnesium stearate.
Film coat: hypromellose, titanium dioxide (E171), lactose monohydrate, glycerol triacetate
What Revatio looks like and contents of the pack
Revatio film-coated tablets are white and round in shape. The tablets are marked with “PFIZER” on
one side and “RVT 20” on the other. The tablets are provided in blister packs containing 90 tablets
(15 tablets per blister strip).
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Pfizer Limited , Sandwich, Kent , CT13 9NJ, United Kingdom.
Manufacturer:
Pfizer PGM , Zone Industrielle, 29 route des Industries , 37530 Poce-sur-Cisse, France.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België /Belgique / Belgien
Luxembourg/Luxemburg
Pfizer S.A./N.V.
Pfizer S.A.
Tél/Tel: +32 (0)2 554 62 11
Tél/Tel: +32 (0)2 554 62 11
България Magyarország
Пфайзер Люксембург САРЛ, Клон България
Pfizer Kft.
Тел.: +359 2 970 4333
Tel.: + 36 1 488 37 00
Česká republika
V.J. Salomone Pharma Ltd.
Tel: +420-283-004-111
Tel : + 356 21 22 01 74
Danmark
Nederland
Pfizer ApS
Pfizer bv
Tlf: +45 44 20 11 00
Tel: +31 (0)10 406 43 01
44
Pfizer s.r.o.
Malta
Deutschland
Norge
Pfizer Pharma GmbH
Pfizer AS
Tel: +49 (0)30 550055 51000
Tlf: +47 67 52 61 00
Eesti
Österreich
Pfizer Luxembourg SARL Eesti filiaal
Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 6 405 328
Tel: +43 (0)1 521 15-0
Ελλάδα
Polska
Pfizer Hellas A.E.
Pfizer Polska Sp. z o.o.,
Τηλ: +30 210 678 5800
Tel.: +48 22 335 61 00
España
Portugal
Pfizer S.A.
Laboratórios Pfizer, Lda.
Tel: +34 91 490 99 00
Tel: +351 21 423 5500
France
România
Pfizer
Pfizer România S.R.L.
Tél: +33 (0)1 58 07 34 40
Tel: +40 21 207 28 00
Pfizer Healthcare Ireland
Pfizer Luxembourg SARL
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: 1800 633 363 (toll free)
Tel: + 386 (0) 1 52 11 400
+44 (0)1304 616161
Ísland
Slovenská republika
Icepharma hf.
Pfizer Luxembourg SARL, organizačná zložka
Sími: + 354 540 8000
Tel: +421-2-3355 5500
Italia
Suomi/Finland
Pfizer Italia S.r.l.
Pfizer Oy
Tel: +39 06 33 18 21
Puh/Tel: +358 (0)9 43 00 40
Κύπρος
Sverige
GEO. PAVLIDES & ARAOUZOS LTD,
Pfizer AB
Τηλ: +35722818087
Tel: + 46 (0)8 550 520 00
Latvija
United Kingdom
Pfizer Luxembourg SARL filiāle Latvijā
Pfizer Limited
Tel: +371 670 35 775
Tel: +44 (0)1304 616161
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
.
There are also links to other website about rare diseases and treatments.
45
Ireland
Slovenija
PACKAGE LEAFLET: INFORMATION FOR THE USER
Revatio 0.8 mg/ml solution for injection
Sildenafil
Read all of this leaflet carefully before you are given this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, please ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What Revatio is and what it is used for
2. Before you are given Revatio
3. How Revatio is given
4. Possible side effects
5 How to store Revatio
6. Further information
1. WHAT REVATIO IS AND WHAT IT IS USED FOR
Revatio belongs to a group of medicines called phosphodiesterase type 5 inhibitors.
Revatio brings down pulmonary blood pressure by widening the blood vessels in the lungs.
Revatio is used to treat pulmonary arterial hypertension (high blood pressure in the blood vessels in
the lungs).
Revatio solution for injection is an alternative formulation of Revatio for patients who temporarily
cannot take their Revatio tablets.
2. BEFORE YOU ARE GIVEN REVATIO
You should not be given Revatio
- If you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Revatio.
- If you are taking medicines containing nitrates, or nitric oxide donors such as amyl nitrate
(“poppers”). These medicines are often given for relief of angina pectoris (or “chest pain”).
Revatio can cause a serious increase in the effects of these medicines. Tell your doctor if you
are taking any of these medicines. If you are not certain, ask your doctor or pharmacist.
- If you have recently had a stroke, a heart attack or if you have severe liver disease or very low
blood pressure (< 90/50 mmHg).
- If you are taking a medicine containing ketoconazole or itraconazole (to treat fungal infections)
or containing ritonavir (for HIV).
- If you have ever had loss of vision because of a problem with blood flow to the nerve in the eye
called non-arteritic anterior ischaemic optic neuropathy (NAION).
46
Take special care with Revatio
Tell your doctor
- If you have a severe heart problem.
- If you have
Retinitis pigmentosa
(a rare inherited eye disease).
- If you have sickle cell anaemia (an abnormality of red blood cells), leukaemia (cancer of blood
cells), multiple myeloma (cancer of bone marrow), or any disease or deformity of the penis.
- If you currently have a stomach ulcer, a bleeding disorder (such as haemophilia) or problems
with nose bleeds.
- If your disease is due to a blocked or narrow vein in the lungs rather than a blocked or narrow
artery.
- If you experience sudden decrease or loss of vision, stop taking Revatio and contact your
doctor immediately.
Special considerations for children and adolescents
Revatio should not be given to children and adolescents under the age of 18.
Special considerations for patients with kidney or liver problems
You should tell your doctor if you have kidney or liver problems, as your dose may need to be
adjusted.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
If you are taking other therapies for pulmonary hypertension (e.g. bosentan, iloprost) ask your doctor
or pharmacist for advice before taking Revatio.
If you are taking medicines containing St. John’s Wort (herbal medicinal product), rifampicin (used to
treat bacterial infections), carbamazepine, phenytoin and phenobarbital (used, among others, to treat
epilepsy) please inform your doctor or pharmacist before taking Revatio
If you are taking medicines that inhibit blood clotting (for example warfarin) please inform your
doctor or pharmacist before taking Revatio.
If you are taking medicines containing erythromycin, clarithromycin, telithromycin (these are
antibiotics used to treat certain bacterial infections), saquinavir (for HIV) or nefazodone (for mental
depression), ask your doctor or pharmacist for advice before taking Revatio, as your dose may need to
be adjusted.
If you are taking alpha-blocker therapy for the treatment of high blood pressure or prostate problems,
ask your doctor or pharmacist for advice before taking Revatio.
Pregnancy and breast feeding
If you are pregnant, or think you might be pregnant, ask your doctor or pharmacist for advice before
you are given Revatio. Revatio should not be used during pregnancy unless strictly necessary.
Stop breast feeding when you start Revatio treatment. Revatio should not be given to women who are
breast feeding since it is not known if the medicine passes into the breast milk.
Driving and using machines
Revatio can cause dizziness and can affect vision. You should be aware of how you react to the
medicinal product before you drive or use machinery.
47
3. HOW REVATIO IS GIVEN
Revatio is given as an intravenous injection and will always be given to you by a doctor or a
healthcare professional. Your doctor will determine the duration of your treatment and how much
Revatio intravenous injection you will receive each day and will monitor your response and condition.
The usual dose is 10 mg (corresponding to 12.5 ml) three times a day.
A Revatio intravenous injection will be given to you instead of your Revatio tablets.
If you receive more Revatio than you should
If you are concerned that you may have been given too much Revatio, tell your doctor or another
healthcare professional immediately.
If you miss a dose of Revatio
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be
missed. However tell your doctor or pharmacist if you think that a dose has been forgotten.
A double dose should not be given to make up for a forgotten dose.
If you stop use of Revatio
Suddenly stopping your treatment with Revatio may lead to your symptoms getting worse. Your
doctor may reduce the dose over a few days before stopping completely.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Revatio can cause side effects, although not everybody gets them.
Side effects reported in a clinical trial with intravenous Revatio were similar to those reported in
clinical trials with Revatio tablets. In clinical trials the side effects reported commonly (seen in less
than 1 in 10 but more than 1 in 100 patients) were facial flushing, headache, low blood pressure and
nausea. In clinical trials side effects reported commonly (seen in less than 1 in 10 but more than
1 in 100 patients) by patients with pulmonary arterial hypertension were facial flushing and nausea.
In clinical trials with Revatio tablets side effects reported very commonly (seen in more than 1 in 10
patients) were headache, facial flushing, indigestion, diarrhoea and limb pain.
Other side effects with Revatio tablets reported commonly (seen in less than 1 in 10 but more than 1
in 100 patients) included: infection under the skin, flu-like symptoms, sinusitis, anaemia, fluid
retention, difficulty sleeping, anxiety, migraine, tremor, pins and needles, burning sensation, reduced
skin sensation, bleeding at the back of the eye, effects on vision, blurred vision and light sensitivity,
effects on colour vision, eye irritation, bloodshot eyes /red eyes, vertigo, bronchitis, nosebleed, runny
nose, cough, stuffy nose, stomach inflammation, gastroenteritis, heartburn, piles, abdominal
distension, dry mouth, hair loss, redness of the skin, night sweats, muscle aches, back pain and
increased body temperature.
Other side effects with Revatio tablets reported less commonly (seen in less than 1 in 100 but more
than 1 in 1000 patients) included: reduced sharpness of vision, double vision, abnormal sensation in
the eye and breast enlargement in men.
Skin rash has also been reported.
Sudden decrease or loss of hearing has been reported.
Decreased blood pressure has been reported.
Revatio contains the same active substance, sildenafil, that is used to treat men with male erectile
dysfunction (MED). Sildenafil belongs to a class of medicine called phosphodiesterase type 5 (PDE5)
48
inhibitors. When used to treat MED, the following visual side effects have been reported with PDE5
inhibitors, including sildenafil: partial, sudden, temporary, or permanent decrease or loss of vision in
one or both eyes.
Prolonged and sometimes painful erections have been reported after taking sildenafil. If you have
such an erection, which lasts continuously for more than 4 hours, you should contact a doctor
immediately.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist
5. HOW TO STORE REVATIO
Keep out of the reach and sight of children.
Do not use Revatio after the expiry date which is stated on the vial label and carton. The expiry date
refers to the last day of that month.
Revatio does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Revatio contains
The active substance is sildenafil. Each ml of solution contains 0.8 mg of sildenafil (as citrate).
Each 20 ml vial contains 10 mg sildenafil (as citrate).
The other ingredients are glucose and water for injections.
What Revatio looks like and contents of the pack
Each pack of Revatio solution for injection contains one 20 ml clear glass vial, which is closed with a
chlorobutyl rubber stopper and an aluminium seal.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Pfizer Limited , Sandwich, Kent , CT13 9NJ, United Kingdom.
Manufacturer:
Pfizer PGM , Zone Industrielle, 29 route des Industries , 37530 Poce-sur-Cisse, France.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België /Belgique / Belgien
Luxembourg/Luxemburg
Tél/Tel: +32 (0)2 554 62 11
Tél/Tel: +32 (0)2 554 62 11
49
Pfizer S.A./N.V.
Pfizer S.A.
България Magyarország
Пфайзер Люксембург САРЛ, Клон България Pfizer Kft.
Тел.: +359 2 970 4333
Tel.: + 36 1 488 37 00
Česká republika
Malta
Pfizer s.r.o.
V.J. Salomone Pharma Ltd.
Tel: +420-283-004-111
Tel : + 356 21 22 01 74
Danmark
Nederland
Pfizer ApS
Pfizer bv
Tlf: +45 44 20 11 00
Tel: +31 (0)10 406 43 01
Deutschland
Norge
Pfizer Pharma GmbH
Pfizer AS
Tel: +49 (0)30 550055 51000
Tlf: +47 67 52 61 00
Pfizer Luxembourg SARL Eesti filiaal
Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 6 405 328
Tel: +43 (0)1 521 15-0
Ελλάδα
Polska
Pfizer Hellas A.E.
Pfizer Polska Sp. z o.o.,
Τηλ: +30 210 678 5800
Tel.: +48 22 335 61 00
España
Portugal
Pfizer S.A.
Laboratórios Pfizer, Lda.
Tel: +34 91 490 99 00
Tel: +351 21 423 5500
France
România
Pfizer
Pfizer România S.R.L.
Tél: +33 (0)1 58 07 34 40
Tel: +40 21 207 28 00
Ireland
Slovenija
Pfizer Healthcare Ireland
Pfizer Luxembourg SARL
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: 1800 633 363 (toll free)
Tel: + 386 (0) 1 52 11 400
+44 (0)1304 616161
Ísland
Slovenská republika
Sími: + 354 540 8000
Pfizer Luxembourg SARL, organizačná zložka
Pfizer Italia S.r.l.
Suomi/Finland
Tel: +39 06 33 18 21
Puh/Tel: +358 (0)9 43 00 40
Κύπρος
Sverige
GEO. PAVLIDES & ARAOUZOS LTD,
Pfizer AB
Τηλ: +35722818087
Tel: + 46 (0)8 550 520 00
Latvija
United Kingdom
Pfizer Luxembourg SARL filiāle Latvijā
Pfizer Limited
Tel: +371 670 35 775
Tel: +44 (0)1304 616161
50
Eesti
Österreich
Icepharma hf.
Tel: +421-2-3355 5500
Italia
Pfizer Oy
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
.
There are also links to other website about rare diseases and treatments.
51
Source: European Medicines Agency
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