1) Inhaled iloprost is a prostacyclin analog approved for treatment of pulmonary arterial hypertension. It works by selectively dilating pulmonary arteries and improving ventilation/perfusion matching in the lungs. 2) Clinical studies have shown inhaled iloprost improves exercise capacity and functional class when used alone or in combination with other PAH therapies like bosentan. It also delays time to clinical worsening. 3) When used with sildenafil, inhaled iloprost and oral sildenafil act synergistically to cause strong pulmonary vasodilation, further improving outcomes in patients with severe PAH.

1. Usefulness and Practicality
Sarfraz Saleemi MD
King Faisal Specialist Hospital & Research Center

2. Pulmonary hypertension - historical perspective
• Ibn Nafees – described pulmonary circulation in ~1250
• Dresdale et al, 1951
– Reported three patients with unexplained pulmonary hypertension
– Clinical, hemodynamic, and pathological features
– Coined the term Primary Pulmonary Hypertension (PPH )
– First attempt at treatment using tolazoline
(Priscoline), an adrenergic inhibitor
Dresdale, Am J Med, 1951
Dresdale, Bull NY Acad Med, 1954

3. Humbert M et al. N Engl J Med. 2004;351:1425-1436.
Targets for current PAH-specific therapy
Big Endothelin
Endothelin-
converting
Enzyme
Endothelin
Receptor A
Endothelin
Receptor B
Vasoconstriction
and
Proliferation
Endothelin
Receptor
Antagonists
Endothelin-1
Endothelin Pathway
Arginine
Nitric Oxide
Synthase
Vasodilatation
and
Antiproliferation
Nitric Oxide
cGMP Exogenous
Nitric Oxide
Phosphodiesterase Type-5
Phosphodiesterase
Type-5 Inhibitors
Nitric Oxide Pathway
Arachidonic Acid
Prostacyclin
Synthase
Vasodilatation
and
Antiproliferation
Prostacyclin
cAMP
Prostacyclin
Derivatives
Prostacyclin
Derivatives
Prostacyclin Pathway

4. Group 1 PAH

5. <1995 1995 2001 2002 2004 2005 2007 2009 2013
CCB
Anticoagulation
Digitalis
Diuretics
IV Epoprostenol
Bosentan
SC Treprostenol
IV Treprostenol
Inhaled
Iloprost
Sildenafil
Ambrisartan
Tadalafil
Inhaled
Treprostinil
Macitentan
Riociguat
Pulmonary Hypertension Treatment Timeline
IV Sildenafil

6. Dysregulated prostacyclin pathway
in pulmonary hypertension
Voltage gated
K+ channel

7. Reduced prostacyclin synthase in PH
Tuder et al. Am J Respir Crit Care Med 1999,159:1925

8. Pharmacological targets of prostacyclin
Arteries
Smooth muscle cells
Fibroblasts
Endothelial cells
Leucocytes
Monocytes, macrophages,
polymorphonuclear cells,
T cells
Platelets
Gomberg-Maitland M, Olschewski H. Eur Respir J 2008;31:891–901.
Vasodilatation
Anti-
inflammation
MAPK
iNOS
 Matrix
secretion
Anti-
proliferation
Anti-
coagulation
Prostacyclin
Anti-inflammatory/Anti-proliferative

9. Prostacyclins for PH
Prostacyclin Approved
IV Epoprostenol iPAH, PAH-CTD (USA, Canada) 1995
PAH (EU) 1996
Inhaled Iloprost PAH (USA) 2004
iPAH (EU)
IV Iloprost iPAH, PAH-CTD, CTEPH (New Zealand)
SC Treprostenol PAH (USA, Canada) 2002
iPAH (EU)
IV Treprostenol PAH (USA, Canada) 2004
Inhaled Treprostenol PAH (USA) 2009
Beraprost oral PAH (Japan, Korea)
Treprostinil oral – resubmitted for approval in Sep 2013
awaiting response in March 2014
Epoprostenol- Discovered in 1976 by the Nobel Prize-winning team of John Vane

10. Inhaled Prostacyclins –selective action
muscular
Partly muscular
Partly intermediate
intermediate
Pericyte level
0.5–3 μm

11. 1. Olschewski H et al. Ann Intern Med 1996;124:820–24;
2. Olschewski H et al. Chest 2003;124:1294–304;
3. Bayer Pharma AG. Ventavis (inhaled iloprost) summary of product characteristics, 2012.
Inhaled iloprost
3
4
5
50
75
CO
(L/min)
PAP
(mmHg)
MAP
(mmHg)
0 30 60 90
Minutes
MAP
PAP
CO
120
80
2.8 μg of iloprost over 15-minute
inhaled Prostacyclin: selective action

12. inhaled Prostacyclin: selective action
No significant V/Q mismatch
Selectively dilates pulmonary arteries vs systemic arteries
Selectively dilates arteries in well-ventilated vs poorly ventilated areas
.
1. Ghofrani HA. Nat Rev Drug Discov 2006;5:689–702
2. Krug S et al. Vasc Health Risk Manag 2009;5:465–74
3. Olschewski H et al. Ann Intern Med 1996;124:820–4
Normal lung: V/Q matching PH lung: V/Q mismatch
Blood
flow
Efficient
oxygenation
Blood
flow
Poor
oxygenation

13. Chest 2003;124;1294-1304
inhaled Prostacyclin: selective action

14. FDA approved inhaled Prostacyclins
Iloprost
Treprostinil

15. ACCF/AHA Consensus PAH Treatment Algorithm
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Atrial septostomy
Lung transplant
Reassess – consider
combo-therapy
ERAs or PDE-5 Is (oral)
Epoprostenol or Treprostinil (IV)
Iloprost (inhaled)
Treprostinil (SC)
No
Anticoagulate ± Diuretics ± Oxygen
± Digoxin
Sustained
Response
Positive
Oral CCB
Continue CCB
Yes
Negative
Lower Risk
Epoprostenol or Treprostinil IV
Iloprost (inhaled)
ERAs or PDE-5 Is (oral)
Treprostinil (SC)
Higher Risk
Investigational Protocols
Acute Vasoreactivity Testing

16. Inhaled Iloprost
• Iloprost is a carbacyclin analog of prostacyclin
• Plasma half-life of 20-30 min
• Dose 2.5-5 μg 6-9 times
• Aerosolized particles (median diameter 0.5–3 μm)

17. Apprved Nebulizer Devices for Iloprost
Halolite prodose I-NEB Venta-NEB

18. Inhaled iloprost
Compact, portable, lightweight,
hand-held nebulizer
Runs on 2 AA batteries, Accurate,
Quiet.
Vibrating Mesh Technology.
Continuous Delivery system.
Omron- MicroAir- NE-U22VThe I-neb™ AAD® system
• Compact, portable, lightweight,
hand-held nebulizer
• Delivers precise individualized
dosing with continuous monitoring
and adjustment

19. Inhaled iloprost – Dose adjustment
Dose per inhalation session: 2.5 µg or 5 µg
Frequency of dosing?
Bayer Pharma AG. Ventavis (inhaled iloprost) summary of product characteristics, 2012.
Initiate
inhaled iloprost
2.5 µg dose
Uptitrate
inhaled iloprost
5 µg dose
Well
tolerated?
Well
tolerated?
Poorly
tolerated?
Maintain 5 µg
Downtitrate: 2.5 µg
6–9 inhalations
per day
According to individual
need and tolerability

20. Idiopathic Pulmonary Arterial Hypertension and
Inhaled Iloprost: Good Night Rebound Effects?
Duration of action (30–120 min)
??Risk of rebound pulmonary
hypertension (RPH) at night during
treatment free period.
5 IPAH patients (NYHA III) on chronic
iloprost treatment .
Hemodynamics by a Swan-Ganz
catheter during day and night
No significant RPH during the
off-medication time at night
PAP and PVR did not exceed the
maximal day time values.
Respiration 2007;74:498–502

21. Lack of desensitization
• Inhaled iloprost avoids continuous receptor activation and
desensitization of acute vasodilatation response does not occur
• Acute hemodynamic response is maintained for many
months
1. Schermuly RT et al. Respir Res 2007;8:4;
2. 2. Nilius SM et al. FEBS Lett 2000;484:211–16;
3. Olschewski H et al. Intensive Care Med 1998;24:631–4.
Pre-inhalation
Post-inhalation
0
mPAP(mmHg)
1
20
40
180
Day
60
360
0
PVR(dyn•s•cm-5)
1
500
1500
180
Day
2000
360
1000
2500

22. Overview of published clinical studies
1. Olschewski H et al. N Engl J Med 2002;347:322–9; 2. Olschewski H et al. Respir Med 2010;104:731–40;
3. Hoeper MM et al. N Engl J Med 2000;342:1866–70; 4. McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63;
5. Ghofrani HA et al. Ann Intern Med 2002;136:515–22; 6. Ghofrani HA et al. J Am Coll Cardiol 2003;42:158–64.
Study name Patients Duration Key result
Monotherapy
AIR FC III/IV
(n=203)
12 weeks
Significant treatment benefit with
iloprost in patients with severe PAH
AIR-2 FC II/III/IV
(n=63)
2 years
Sustained inhaled iloprost improves
predicted 2 year survival
Long-term3 FC III/IV
(n=24)
1 year Clinical benefits of inhaled iloprost are
sustained over 1 year of therapy
Combination therapy
STEP (bosentan
+ iloprost)
FC II/III/IV
(n=67)
12 weeks Inhaled iloprost + bosentan is
well tolerated and effective
Acute iloprost +
sildenafil
FC III/IV
(n=30)
Acute dose Inhaled iloprost + sildenafil
acts synergistically to induce
strong pulmonary vasodilation
Iloprost +
sildenafil
FC III/IV
(n=14)
1 year Inhaled iloprost + sildenafil improves
outcomes in patients with severe PAH

23. -40
-20
0
20
40
1 2 3 4
Inhaled
Iloprost
Placebo
AIR study
Olschewski H et al. N Engl J Med 2002;347:322–9.
Improvement in 6MWD
Meanchangeindistancewalked(m)
Baseline Week 4 Week 8 Week 12
• In IPAH patients on inhaled iloprost, average increase in 6MWD
was 58.8 m longer than for placebo-treated patients
Δ6MWD =36 m
p=0.004

24. STEP study
Inhaled
iloprost
50
25
Meanchangein
distancewalked
(m)
Baseli
ne
Week
4
Week
8
Week
12
Placeb
o0
-25
Δ6MWD =26 m
p=0.051
McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63.
(Bosentan + inhaled iloprost)

25. AIR study: Aerosilized Iloprost Randomized study
Olschewski H et al. N Engl J Med 2002;347:322–9.
Combined primary endpoint:
• Improvement by ≥1 NYHA FC
• ≥10% improvement in 6MWD
• no deterioration or death
0
5
10
15
20
Inhaled
Iloprost
Patients(%)
Placebo
5%
p=0.007
17%
Significant improvement in the combined primary endpoint with
inhaled iloprost vs placebo

26. Efficacy (time to clinical worsening)
• No patients receiving bosentan + inhaled iloprost experienced
clinical worsening, compared with 15% of patients receiving
bosentan + placebo (p=0.02)
McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63.
Bosentan + inhaled iloprost1.00
0.75
0.50
0.25
0.00
Withoutclinical
deterioration
(percentageofpatients)
Bosentan + placebo
Baseline Week 4 Week 8 Week 12
Clinical worsening defined as: death due to PAH, worsening PAH leading to
hospitalization or early elimination from the study, necessary additional PAH-specific
therapy, lung transplant or atrial septostomy
STEP study

27. STEP open-label extension:
Clinical worsening
• A 3-month delay in adding prostacyclin therapy may negatively
affect the clinical result
Olschewski H et al. Eur Resp Rev 2009;18:29–34.
Placebo+ Inhaled iloprost
Bosentan
0 3 6 9 12
Inhaled iloprost
Bosentan
43%
23%
Patients with
clinical worsening
after one year
Patients with
clinical worsening
after one year
Months

28. Addition of sildenafil to inhaled iloprost
further increased exercise capacity
inhaled iloprost
+ oral sildenafil
sil-ilo
9-12 mo
treatment interval
18 + 4 months
sil-ilo
6 mo
sil-ilo
3 mo
pre-sililo
3 mo
Baseline
180
200
220
240
260
280
300
320
340
360
380
400
6-minutewalkdistance(m)
p=0.002
p=0.014
p=0.002
+
+
+
Ghofrani HA et al. J Am Coll Cardiol 2003;42:158–64.

29. • Inhaled iloprost alone and oral
sildenafil alone showed similar
efficacy (pulmonary vasodilatory
potency)
• Inhaled iloprost and oral sildenafil
together acted synergistically to
cause strong pulmonary
vasodilatation
Acute use study (sildenafil + inhaled iloprost):
Hemodynamic outcomes
Ghofrani HA et al. Ann Intern Med 2002;136:515–22.
PVR
(%changefrombaseline)
60
NO Iloprost Sildenafil 50 mg
0 60 0 120
-30
-20
-10
0
-50
-40
Time (min)
n = 8
180
NO
0 60 0 60 120
Time (min)
n = 8
Iloprost Sildenafil 50 mg
Iloprost

30. Inhaled Iloprost in acute right heart failure due to PAH
Age (y) 72 59 52 65 55 48 63
Baseline
PH
therapy
SC
treprostinil
Bosentan SC
treprostinil
SC
treprostinil
SC
treprostinil
Sitaxentan Sitaxentan
NT-
proBNP
9,690 10,636 9,340 8,964 1,265 20,239 35,000
J Card Fail. 2011 October; 17(10): 813–818
(7 patients) Hourly inhaled iloprost for 12 hours

31. Open-label extension of the AIR study – 71 patients
NYHA FC improved in 41% at 1 year & 76% at 3 year
Survival rate:
83% at 1 yr
78% at 2 yrs
58% at 5 yrs (Estimated survival without treatment 32%)
www.clinicalstudyresults.org/
drugdetails/?company_id573&indication_id5854&sort5c.
company_name&page51&drug_id52423 December 16, 2008
Long term efficacy of Iloprost
Survival

32. Transition from Parenteral prostacyclin to
inhaled Iloprost (n=37)
Pulmonary circulation April-Iune 2013

33. iloprost is not approved for use in children
Data on its use in the pediatric PAH population is limited.
22 children median age 11.5 years (range, 4.5–17 i PAH & PAH-CHD
19 On background PAH-specific therapy
Duration 6 months
WHO FC improved in 35% , decreased in 15% and unchanged in 50%
Bronchopasm and compliance issue were major limitations
Ivy et al. (2008)
.
A review of 28 studies (most case series) 195 children
Inhaled iloprost has acute effects similar to those of inhaled NO and might
have a role in the short-term treatment of pediatric PH, including neonates.
This application of inhaled Iloprost is useful especially in countries where
inhaled NO is not available
Mulliganand Beghetti,2011
Inhaled Iloprost in Children

34. Cost effectiveness of inhaled Iloprost (3 year analysis)
Appl Health Econ Health Policy 2012; 10 (3): 175-188

35. Inhaled Treprostinil (Tyvaso)
Administered 4 times daily with Optineb
Maximum 9 breaths 4 times a day
Each breath 6 microgram
1 ampule of inhaled treprostinil enough for the day
whether 3 breaths or 9 breaths 4 times a day.
Discard the remaining dose after last dose of the day
Needs washing of optineb accessories everyday.

36. %
0
3.0
5.0
10
TRIUMPH
[TReprostinil sodium Inhalation Used in the Management of Pulmonary Hypertension]
• 6-minute walk distance (6MWD) ↑ in
treprostinil vs. placebo at 12 weeks (21.6 vs.
3.0 m, p = 0.0004); noted as early as 6 weeks
(p = 0.0001)
• No difference in Borg dyspnea score, NYHA
class, PAH signs and symptoms (p = NS)
• Clinical worsening similar (3% vs. 5%, p = NS)
Trial design: Patients with pulmonary arterial hypertension (PAH) who were
symptomatic on bosentan or sildenafil were randomized to either inhaled
treprostinil or placebo. Clinical outcomes were assessed at 12 weeks.
Results
Conclusions
•Inhaled treprostinil was associated with
improved 6MWD as compared with placebo
in symptomatic patients with PAH already
on bosentan or sildenafil
McLaughlin W, et al. J Am Coll Cardiol 2010;55:1915-22
Treprostinil
(n = 115)
Placebo
(n = 120)
(p = NS)
15
30
21.6
3.0
m
0
6MWD Clinical worsening
5
(p = 0.0004)

37. Rapid transition from Inhaled Iloprost to Inhaled Treprostinil (n-73)
Cardiovascular Therapeutics 31 (1), 38-44 (Feb 2013)

38. Treatment satisfaction is associated with improved quality of
life in patients transitioned to inhaled treprostinil from iloprost
Chen et al. Health and Quality of Life Outcomes 2013, 11:31
http://www.hqlo.com/content/11/1/31
66 subjects with PAH in a single-arm, open-label
Multicenter trial of iTRE following transition from iILO
Treatment Satisfaction Questionnaire for Medication (TSQM)

39. MDI-Treprostenol vs Nebulized
Pulmonary Pharmacology & Therapeutics 22 (2009) 50–56
39 consecutive patients with moderate to severe PAH were enrolled in an
open label, placebo controlled trial

40. Treatment of inhaled Treprostinil induced cough
Inhaled anticholinergic
Inhaled steroids
Oral phenol-based analgesic sprays (eg,Chlorasept)
Drinking very cold or warm water before a treatment
Reducing number of breaths per treatment
• Cough
• Flushing
• Headache
• Trismus
• Insomnia
• Nausea
Side Effects of inahled Prostacyclin

41. • Hypersensitivity to the drug
• Patients with an increased risk of hemorrhage
• Severe IHD or unstable angina
• Myocardial infarction within the last 6 months
• CVA (TIA or stroke) in the previous 3 months
• Veno-occlusive disease
Relative contraindications to inhaled prostacyclins

42. Summary
• Inhaled Prostacyclin is an effective treatment of
pulmonary arterial hypertension
• Inhaled Prostacyclin causes rapid improvement of
pulmonary hemodynamic which is maintained even after
long duration due to lack of desensitization
• Inhaled Prostacyclin causes vasodilatation of the well
ventilated parts of lung so results in better oxygenation
• Few systemic adverse effects due to selective action
• Avoids infection and localized site pain of parenteral
therapy
• No involvement of CYP450 so minimal potential for
interaction with drugs metabolized by the liver
• Frequent dosaging and preparation time is a major
disadvantage
• Cough and facial flushing are the commonest side effects

43. Thanks
43