Updates on Pulmonary

Hypertension: What current

evidence recommends

PP-REV-IDN-0012-SEP-2020
 Definition
Updates in parameter based on 6 th World Symposium on PH
Previous Definition

PH has been defined as mPAP ⩾25 mmHg measured by right

heart catheterization (RHC) in the supine position at rest
(1st World Symposium on Pulmonary Hypertension (WSPH) , WHO Geneva 1973)

• In the report of the meeting, it was recognized that this upper limit of
normal mPAP of 25 mmHg was somewhat empirical and arbitrarily
defined
• This definition remained unchanged during the subsequent WSPH
meetings from 1998 to 2013
PH= Pulmonary hypertension; mPAP= mean Pulmonary Arterial Pressure; RHC= Right heart catheterization; WSPH= Would Symposium on Pulmonary Hypertension; WHO= World heart Organization

Simonneau G, et al. Eur Respir J 2019;53:1801913

 Definition
Updates in parameter based on 6 th World Symposium on PH
Current Definition

CO- cardiac output

• A mPAP of 20 mmHg should be considered as the upper limit of normal value.

• Pre-capillary PH is best defined by the concomitant presence of mPAP >20 mmHg, PAWP ⩽15 mmHg and PVR ⩾3
WU, emphasising the need for RHC with mandatory measurement of CO and accurate measurement of PAWP.
Simonneau G, et al. Eur Respir J 2019;53:1801913
 Pathogenesis of PAH
RISK FACTORS AND VASCULAR INJURY DISEASE PROGRESSION
ASSOCIATED CONDITIONS
Endothelial dysfunction
CTD
CHD ↓NO synthase
SUSCEPTIBILITY
Portal hypertension
BMPR2 mutation
↓PGI2 production
HIV
Other genetic factors ↑Thromboxane production
Drugs and toxins
Pregnancy ↑ET-1 production
Smooth muscle
Vascular smooth muscle dysfunction hypertrophy

Adventitial and intimal

Adventitia proliferation
Smooth muscle
Media hypertrophy In situ
thrombosis
Intima

Early intimal Plexiform

proliferation lesion

Vasoconstriction Advanced vascular lesion

Reversible Irreversible
Normal disease disease
BMPR2 = bone morphogenetic protein receptor type 2 ; CHD = congenital heart disease; CTD = connective tissue disease;
ET-1 = endothelin-1; HIV = human immunodeficiency virus; NO = nitric oxide; PAH = pulmonary arterial hypertension; PGI2 = prostacyclin

Adapted from Gaine S. JAMA 2000;284:3160–8.

 PAH Survival
PAH survival correlates with NYHA functional class 1 PAH survival based on aetiology 2,3

100
90 1
Median survival time (months)

0.9 CHD2
80
0.8
IPAH2
70 0.7

Survival (%)
CVD2
60 0.6
58.6 HIV3
0.5
50 0.4
40 0.3
0.2
30 31.5 0.1
20 0
1 2 3 4 5
10
6 Years
0
FC I & II FC III FC IV
FC = functional class; PAH = pulmonary arterial hypertension; NYHA = New CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human
York Heart Association immunodeficiency virus; IPAH = idiopathic pulmonary arterial hypertension; PAH =
pulmonary arterial hypertension
1. D'Alonzo GE, et al. Ann Intern Med 1991;115:343–9.
2. McLaughlin VV, et al. Chest 2004;126 (Suppl 1):78–92.
3. Degano B, et al. AIDS 2010; 24: 67-75.
 Clinical Classification
The general purpose of clinical classification of PH is to categorize clinical conditions associated with PH based on
similar pathophysiological mechanisms, clinical presentation, hemodynamic characteristics and therapeutic
management.

1. PAH
• 1.1 Idiopathic PAH
• 1.2 Heritable PAH
• 1.3 Drug- and toxin-induced PAH
• 1.4 PAH associated with:
• 1.4.1 Connective tissue disease
• 1.4.2 HIV infection
• 1.4.3 Portal hypertension
• 1.4.4 Congenital heart disease
• 1.4.5 Schistosomiasis
• 1.5 PAH long-term responders to calcium channel blockers
• 1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement
• 1.7 Persistent PH of the newborn syndrome
PAH = pulmonary arterial hypertension, HIV = human immunodeficiency virus, PVOD =
Simonneau G, et al. Eur Respir J 2019;53:1801913 pulmonary veno-occlusive disease, PCH = pulmonary capillary haemangiomatosis
 Clinical Classification
2. PH due to left heart disease
• 2.1 PH due to heart failure with preserved LVEF
• 2.2 PH due to heart failure with reduced LVEF
• 2.3 Valvular heart disease
• 2.4 Congenital/acquired cardiovascular conditions leading to post-capillary PH

3 PH due to lung diseases and/or hypoxia

• 3.1 Obstructive lung disease
• 3.2 Restrictive lung disease
• 3.3 Other lung disease with mixed restrictive/obstructive pattern
• 3.4 Hypoxia without lung disease
• 3.5 Developmental lung disorders
Simonneau G, et al. Eur Respir J 2019;53:1801913 PH= Pulmonary hypertension, LVEF = left ventricular ejection fraction
 Clinical Classification
4 PH due to pulmonary artery obstructions
• 4.1 Chronic thromboembolic PH
• 4.2 Other pulmonary artery obstructions
5 PH with unclear and/or multifactorial mechanisms
• 5.1 Haematological disorders
• 5.2 Systemic and metabolic disorders
• 5.3 Others
• 5.4 Complex congenital heart disease

Simonneau G, et al. Eur Respir J 2019;53:1801913 PH= Pulmonary hypertension

 Functional classification of PH modified after the NYHA
functional classification according to WHO 1998
Description
Class I Patients with pulmonary hypertension but without resulting limitation of
physical activity. Ordinary physical activity does not cause undue dyspnea or
fatigue, chest pain, or near syncope
Class II Patients with pulmonary hypertension resulting in slight limitation of
physical activity. They are comfortable at rest. Ordinary physical activity
causes undue dyspnea or fatigue, chest pain, or near syncope.

Class III Patients with pulmonary hypertension resulting in marked limitation of

physical activity. They are comfortable at rest. Less than ordinary activity
causes undue dyspnea or fatigue, chest pain, or near syncope.

Class IV Patients with pulmonary hypertension with inability to carry out any physical
activity without symptoms. These patients manifest signs of right heart
failure. Dyspnea and/or fatigue may even be present at rest. Discomfort
is increased by any physical activity.

PH = pulmonary hypertension; NYHA = New York Heart Association; WHO = World Health Organization

Galiè N, et al. Eur Heart J 2009;30:2493–537.

 PAH symptoms 1,2

• The most common symptoms of PH can also be caused by other more common
medical problems, such as asthma or chronic obstructive pulmonary disease
(COPD). Therefore, diagnosing PH is difficult and requires a specialist.1
• Physical examination signs can include visible or enlarged veins on the side of the
neck, irregular heart sounds or swelling in the abdomen or legs and feet.1
Presenting symptoms1,2
21.9%

26.7% 15% 22.2% 86.1% 12.9%

1. Brown LM, et al. Chest. 2011;140(1):19-26

2. About Pulmonary Hypertension. Available at https://phassociation.org/patients/aboutph/. Accessed on May 2020
PH= Pulmonary hypertension
 Diagnosis

Adapted from Frost A, et al. 2019

PH= Pulmonary hypertension, V/Q = ventilation/perfusion;

Frost A, et al. Eur Respir J 2019;53:1801904 CTEPH = chronic thromboembolic Pulmonary hypertension
 Diagnosis

Adapted from Frost A, et al. 2019

PH= Pulmonary hypertension , CTEPH = chronic thromboembolic PH,

Frost A, et al. Eur Respir J 2019;53:1801904 V/Q = ventilation/perfusion, RHC = right heart catheterization
 Diagnosis - Echocardiographic

Frost A, et al. Eur Respir J 2019;53:1801904 PH= Pulmonary hypertension

 Diagnosis - Echocardiographic

Frost A, et al. Eur Respir J 2019;53:1801904

 Echocardiographic probability of pulmonary hypertension in symptomatic
patients with a suspicion of pulmonary hypertension

Galiè N, et al. Eur Respir J.2015;46:903-975

PH= Pulmonary hypertension
 Risk Stratification

6MWD: 6-minute walking distance; BNP: brain natriuretic peptide; CI: cardiac index; CMR: cardiac magnetic resonance; NT-proBNP: N-terminal pro-brain natriuretic
peptide; pred.: predicted; RA: right atrium; RAP: right atrial pressure; SvO2: mixed venous oxygen saturation; VE/VCO2: ventilatory equivalents for carbon dioxide;
VO2: oxygen consumption; WHO: World Health Organization

Galiè N, et al. Eur Respir J.2015;46:903-975

 Risk Stratification and Medical Therapy of PAH – LOW RISK

PAH: pulmonary arterial hypertension; IPAH:

idiopathic PAH; HPAH: heritable PAH; DPAH:
drug-induced PAH; CCB: calcium channel
blocker; PCA: prostacyclin analogue; PH:
pulmonary hypertension

Galie N, et al. Eur Respir J 2019;53:1801889

 Risk Stratification and Medical Therapy of PAH – HIGH RISK

PAH: pulmonary arterial hypertension; IPAH:

idiopathic PAH; HPAH: heritable PAH; DPAH:
drug-induced PAH; CCB: calcium channel
blocker; PCA: prostacyclin analogue; PH:
pulmonary hypertension

Galie N, et al. Eur Respir J 2019;53:1801889

 Risk Stratification and Medical Therapy of PAH – INTERMEDIATE
RISK

PAH: pulmonary arterial hypertension; IPAH:

idiopathic PAH; HPAH: heritable PAH; DPAH:
drug-induced PAH; CCB: calcium channel
blocker; PCA: prostacyclin analogue; PH:
pulmonary hypertension

Galie N, et al. Eur Respir J 2019;53:1801889

 PAH Treatment Molecular Pathway

Humbert M et al. NEJM 2004

 Therapy for Pulmonary Arterial Hypertension in Adults Update of the CHEST
Guideline and Expert Panel Report

Klinger et al. Chest 2019; 155(3):565-586

 Recommendations for
efficacy of drug
monotherapy for
pulmonary arterial
hypertension according
to World Health
Organization functional
class

Galie N, et al. Eur Respir J 2015; 46: 903–975

WHO-FC: World Health Organization functional class.
 Recommendations for efficacy of
initial drug
combination therapy for
pulmonary arterial hypertension
(group 1) according to World
Health Organization functional
class.

ERA: endothelin receptor antagonist; i.v.: intravenous; PDE-5i: phosphodiesterase type 5 inhibitor;
WHO-FC: World Health Organization functional class; s.c.: subcutaneous
Galie N, et al. Eur Respir J 2015; 46: 903–975
 Recommendations for efficacy of sequential drug combination therapy for
pulmonary arterial hypertension according to WHO functional class.

Galie N, et al. Eur Respir J 2015; 46: 903–975 ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase type 5 inhibitor; WHO-FC: World
Health Organization functional class
 SUPER-1: Sildenafil Use in Pulmonary Arterial HypERtension
study design
Placebo, n=70

Sildenafil 20 mg (TID), n=69

Screening and Titration to sildenafil 80 mg
randomisation (TID), n=259
Sildenafil 40 mg (TID), n=68

Sildenafil 80 mg
(40 mg:7 days) (TID), n=71

0 2 4 6 8 10 12 52

Screening baseline Weeks Titration into extension phase

SUPER-1 SUPER-2
TID = three times a day

Galiè N, et al. New Engl J Med 2005;353:2148–57.

 SUPER-1: improvements in 6MWD

The mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m
(+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons).

Sildenafil 20 mg TID is the licensed dose

Galiè N, et al. New Engl J Med 2005;353:2148–57. 6MWD = 6-minute walk distance; TID = three times a day
 SUPER-1: improvements in all subpopulations
Number of patients
S P
23 23
Baseline Walking Distance <325 m 23 23
26 23
44 43
325 m 41
43
43
43

43 39
IPAH 42 39
46 39
Cause of PAH 20 21
PAH–CTD 18
19
21
21
4 6
PAH–surgical repair 4 6
4 6

22 31
Class I/II 21 31
WHO Functional class 27 31
45 35
Class III/IV 43 35
42 35

30 29
39 29
<Median 31 29
mPAP (mmHg)
Median 36
24
37
37
38 37

Sildenafil 20 mg TID
-20 0 20 40 60 80 100 120 140 160
Sildenafil 40 mg TID Placebo-corrected change in 6MWD (m)
Sildenafil 80 mg TID

Sildenafil 20 mg TID is the licensed dose

CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk
Galiè N, et al. New Engl J Med 2005;353:2148–57. distance; P = placebo; PAH = pulmonary arterial hypertension; PVRI = pulmonary vascular resistance index; S = sildenafil; TID = three times a day
 SUPER-1: improvements – 20 mg sildenafil
Number of patients

S P
6MWD <325 m 23 23

325 m 44 43

IPAH 43 39

Aetiology
PAH–CTD 20 21

PAH–surgical repair 4 6

Class I/II 22 31
Functional class
Class III/IV 45 35

<Median 30 29
mPAP (mmHg)
Median 36 37

-20 0 20 40 60 80 100 120 140 160

Sildenafil 20 mg TID Placebo-corrected change in 6MWD (m)

Sildenafil 20 mg TID is the licensed dose

CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk
distance; P = placebo; PAH = pulmonary arterial hypertension; PVRI = pulmonary vascular resistance index; S = sildenafil; TID = three times a day

Galiè N, et al. New Engl J Med 2005;353:2148–57.

 SUPER-1

Mean Change of Pulmonary Vascular Resistence from

Dose-dependent reductions in mPAP Dose-dependent reductions in PVR
4 200
Pressure from baseline at Week 12 (mmHg)

Placebo
Mean Change of Mean Pilmonary Artery

baseline at Week 12 (dyn•s/cm5)

2 100
Sildenafil 20 mg Sildenafil 40 mg Sildenafil 80 mg
TID TID TID
Placebo 0
0
Sildenafil 20 Sildenafil 40 Sildenafil 80
mg TID mg TID mg TID +49
-2 -100

+0.6 -200
-4
-122 -143
-300 p=0.01 p=0.01
-6 vs placebo vs placebo
-2.1 -2.6
p=0.04 -4.7 -400 -261
-8 p=0.01
vs p<0.001
vs placebo p<0.001
placebo vs placebo
vs placebo

Sildenafil 20 mg TID is the licensed dose

mPAP = mean pulmonary arterial pressure; TID = three times a day; PVR = pulmonary vascular resistance

Galiè N, et al. New Engl J Med 2005;353:2148–57.

 SUPER-1: improvements in WHO FC status
Improvement of WHO FC
(at least 1 functional class)

45%
40% **
*
35% *
30% *
25% *
42%
20% 36%
15% 28%

10%
5% 7%

0%
Placebo 20mg 40mg 80mb

Improvement of WHO FC
Sildenafil 20mg TID is the licensed dose
*placebo-corrected difference, 21 percent; 95 percent confidence interval, 9 to 33 percent; P=0.003
**placebo-corrected difference, 29 percent; 95 percent confidence interval, 16 to 42 percent; P<0.001
***placebo-corrected difference, 35 percent; 95 percent confidence interval, 22 to 48 percent; P<0.001
Galiè N, et al. New Engl J Med 2005;353:2148–57. TID = three times a day
 SUPER-1

Sildenafil 20mg TID is the licensed dose

†Adverse events shown are those reported by 3 percent or more of
patients and those reported more frequently with sildenafil than with
placebo

Galiè N, et al. New Engl J Med 2005;353:2148–57. TID = three times a day
 SUPER-2: Long-Term Treatment with Sildenafil Citrate in
Pulmonary Arterial Hypertension - study design
Titration into extension study

Placebo
Regimen A

Titration
Titration to sildenafil
Sildenafil 20 mg (TID) to sildenafil
40 mg (TID)
Screening and 80 mg (TID)
randomisation
Sildenafil 40 mg (TID)
Regimen B

Dummy titration to sildenafil

Sildenafil 80 mg (TID)
80 mg (TID)

12 weeks 3 years

Double-blind Open-label
Screening baseline extension
phase

SUPER-1 SUPER-2

TID = three times a day

Rubin LJ, et al. Chest 2011;140(5):1274-1283

 SUPER-2: Kaplan-Meier survival estimate
Survival analysis population (%)*
Sildenafil Sildenafil Sildenafil
Survival All Placebo 20 mg TID 40 mg TID 80 mg TID
period n=277 n=70 n=69 n=67 n=71

Percent
1 year 94 86 96 100 93
survived

Percent
2 years 88 81 91 95 86
survived

Percent
3 years 79 68 84 84 78
survived

*Analysis includes 18 patients from the double-blind study who did not enter the extension trial
Sildenafil 20 mg TID is the licensed dose
TID = three times a day

Rubin LJ, et al. Chest 2011;140(5):1274-1283

 SUPER-2: safety
Treatment-related adverse events Total
in ≥5% of subjects No (%) • Perceived treatment related SAEs
Headache 42(16) included:
• Grand mal seizure
Dyspepsia 27(10)
• Hypotension
Diarrhea 21(8) • Drug hypersensitivity
• Urticaria and angioedema
Blurred vision 19(7)
• Gastro-oesophageal reflux disease
Nausea 15(6) • Posterior subcapsular cataract

Abdominal pain 14(5) • Nine patients permanently discontinued

due to perceived sildenafil-related AEs
Abdominal pain upper 13(5)

Rubin LJ, et al. Chest 2011;140(5):1274-1283 SAE = Serious Adverse Event; AE = Adverse Event
 SUPER-2: conclusions
• After 3 years
• 46% of patients maintained or improved 6MWD
• 60% of patients maintained or improved their functional status
• Kaplan-Meier estimated survival was 79%
• Most treatment-related adverse events were mild to moderate in
severity, and included headache, dyspepsia, diarrhoea, blurred vision,
nausea, and abdominal pain

6MWD = 6-minute walk distance

Rubin LJ, et al. Chest 2011;140(5):1274-1283

Lilyasari O, et al. Health Services Research, 2019. 19:573
 Conclusion
• New evidence suggests new threshold for PH with mPAP > 20mmHg.
This new definition would enable earlier detection of PH1
• Echocardiography can be valuable tool in helping to diagnose PAH2
• Risk stratification and assessment of patient prognosis with PAH is
considered as important part of care3
• Sildenafil is proven to be effective in managing pulmonary arterial
hypertension4-5

1. Simonneau G, et al. Eur Respir J 2019;53:1801913

2. Galiè N, et al. Eur Respir J.2015;46:903-975
3. Galie N, et al. Eur Respir J 2019;53:1801889
4. Galiè N, et al. New Engl J Med 2005;353:2148–57
PH= Pulmonary hypertension; mPAP= mean Pulmonary Arterial Pressure; PAH = pulmonary arterial hypertension
5. Rubin LJ, et al. CHEST 2011;140(5):1274-1283
 Product lnformation :
Composition: Revatio, each film-coated tablet contains 20 mg of sildenafil, (as citrate). Indication: Revatio tablets are indicated for treatment of adult patients with pulmonary arterial hypertension (PAH) classified as WHO functional class II and Ill, to improve exercise capacity. Efficacy has
been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. Dosage & Administration Patients using other medicinal products: In general, any dose adjustment should be administered only after a careful benefit-risk assessment.
A downward dose adjustment to 20 mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration wrth more
potent CYP3A2 inhibitors clarithromycin. For the use of sildenafil with the most potent CYP3A4 inhibitors. Dose adjustments for sildenafil may be required when co-administered with CYP3A4 inducers. For adults, the recommended dose is 20 mg three times aday (TID). Physicians should
advise patients who forget to take Revatio to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose. Elderly (> 65 years), Dose adjustments are not required in elderly patients. Renal impairment,
initial dose adjustments are not required in patients with renal impairment, including severe renal impairment (creatinine clearance < 30 ml/min).A downward dose adjustment to 20 mg twice daily should be considered alter a careful benefit-risk assessment only if therapy is not well-
tolerated. Hepatic impairment, initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and B). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.
Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C). Discontinuation of treatment Limited data suggests that the abrupt discontinuation of Revatio is not associated with rebound worsening of PAH. However to avoid the possible occurrence of
sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified monitoring is recommended during the discontinuation period. Method of administration Revatio is for oral use only. Tablets should be taken approximately 6 to 8 hours apart
with or without food. Contraindications: 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, the co-administration of PDE5 inhibitors,
including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension, combination with the most potent of the CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir), 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 conniection or not with previous PDE5 inhibitor exposure, and the safety of sildenafil has not been studied in the following sub-group 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. Warning and Precautions: The efficacy of Revatio has not been established in patients with severe pulmonary arterial
hypertension (functional class IV). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO functional class I PAH. Studies with sildenafil have been performed in forms of PAH related to primary (idiophatic) connective tissue disease associated or
congenital heart disease associated forms of PAH. The use of sildenafil in other forms of PAH is not recommended. The safety of sildenafil has not been studied in patients with known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have
genetic disorders of retinal phosphodiesterases) and therefore its use is not recommended. When prescribing, physicians should carefully consider whether their patients with certain underlying conditions : patients with hypotension, patients with fluid depletion, severe left ventricular
outilow obstruction or autonomic dystunction. In post-marketing experience with sildenafil for male erectile dystunction, 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. 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). If priapism is not treated immediately, penile tissue damage and permanent
loss of potency could result. Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of non-arterilic
anterior ischaemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors. In the event of any sudden visual defect the treatment should be stopped immediately and
alternative treatment should be considered. 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. 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 PAH 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 PAH 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. The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively demonstrated. The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, including Viagra, has not been
studied in PAH patients and such concomitant use is not recommended. Interaction: 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. Co-administration of oral Sildenafil and intravenous epoprostenol has been evaluated. The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg, ambrisentan,
iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration. Population pharmacokinetic analysis of PAH 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. Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil. Co-administration of oral contraceptives (ethinyloestradiol 30 µg and
levonorgestrel 150 µg) did not affect the pharmacokinetic 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. There are no data on the interaction of sildenafil and non-
specific phosphodiesterase inhibitors such as theophylline or dipyridamole. No significant interactions were shown when oral sildenafil (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 oral 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 oral sildenafil at steady state (80 mg three times a
day) resulted in a 50% increase in bosentan AUC (125 mg twice daily). 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 biood 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 biood 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. 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, 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. Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when
PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol30 µg and levonorgestrel150 µg).
Pregnancy & Lactation: Due to lack of data, Revatio should not be used in pregnant woman unless strictly necessary. There are no adequate and well controlled studies in lactating women. Limited data indicate that sildenafil and its active metabolite are excreted into breast milk at very
low levels. Amount ingested by breast milk would not be expected to cause any adverse effects. Mother’s clinical need for Revatio and any potential adverse effects on the breastfed child should carefully assess. Undesirable Effects: Very Common: headache, flushing, diarrhoea, dyspepsia,
pain in extremity, Common: cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis, anaemia, fluid retention, insomnia, anxiety, migraine, tremor, paraesthesia, burning sensation, hypoaesthesia, retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia,
cyanopsia, eye irritation, ocular hyperaemia, vertigo, epistaxis, cough, nasal congestion, gastritis, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth, alopecia, erythema, night myalgia, back pain. Uncommon: visual acuity reduced, diplopia, abnormal
sensation in eye, haematuria. Not known: Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal vascular occlusion, Visual field defect, sudden hearing loss, hypotension, rash, priapism, erection increased. Supply: REVATIO 20 mg, box contains of 6 blisters@ 15film-coated
tablets. Reg No: DKI1690401317A1. Manufactured by FarevaAmboise, Poce-sur-Cisse, France. lmported by PT. Pfizer Indonesia, Jakarta, Indonesia. Storage Do not store above 30oC. Store in the original package in order to protect from moisture. HARUS DENGAN RESEP DOKTER.

Reference: Latest BPOM Approved Revatio film-coated tablet Local Product Document 2020

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