ANNEX I
`
`SUMMARY OF PRODUCT CHARACTERISTICS
`
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`1.
`
`NAME OF THE MEDICINAL PRODUCT
`
`Ventavis 10 microgram/ml nebuliser solution
`Ventavis 20 microgram/ml nebuliser solution
`
`2.
`
`QUALITATIVE AND QUANTITATIVE COMPOSITION
`
`Ventavis 10 microgram/ml nebuliser solution
`1 ml solution contains 10 microgram iloprost (as iloprost trometamol).
`Each ampoule with 1 ml solution contains 10 microgram iloprost.
`Each ampoule with 2 ml solution contains 20 microgram iloprost.
`
`Ventavis 20 microgram/ml nebuliser solution
`1 ml solution contains 20 microgram iloprost (as iloprost trometamol).
`Each ampoule with 1 ml solution contains 20 microgram iloprost.
`
`Excipient with known effect
`Ventavis 10 microgram/ml:
`(cid:120)
`Each ml contains 0.81 mg ethanol 96% (equivalent to 0.75 mg ethanol)
`Ventavis 20 microgram/ml:
`Each ml contains 1.62 mg ethanol 96% (equivalent to 1.50 mg ethanol).
`
`(cid:120)
`
`For the full list of excipients, see section 6.1.
`
`3.
`
`PHARMACEUTICAL FORM
`
`Nebuliser solution.
`
`Ventavis 10 microgram/ml nebuliser solution
`Clear, colourless solution.
`
`Ventavis 20 microgram/ml nebuliser solution
`Clear, colourless to slightly yellowish solution.
`
`4.
`
`CLINICAL PARTICULARS
`
`4.1 Therapeutic indications
`
`Treatment of adult patients with primary pulmonary hypertension, classified as NYHA functional
`class III, to improve exercise capacity and symptoms.
`
`4.2
`
`Posology and method of administration
`
`Drug product
`
`Suitable inhalation device (nebuliser) to be used
`
`Ventavis 10 microgram/ml
`Ventavis 20 microgram/ml
`
`Breelib
`Breelib
`
`I-Neb AAD
`I-Neb AAD
`
`Venta-Neb
`
`Ventavis should only be initiated and monitored by a physician experienced in the treatment of
`pulmonary hypertension.
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`Posology
`
`Dose per inhalation session
`At initiation of Ventavis treatment the first inhaled dose should be 2.5 microgram iloprost as delivered
`at the mouthpiece of the nebuliser. If this dose is well tolerated, dosing should be increased to
`5 microgram iloprost and maintained at that dose. In case of poor tolerability of the 5 microgram dose,
`the dose should be reduced to 2.5 microgram iloprost.
`
`Daily dose
`The dose per inhalation session should be administered 6 to 9 times per day according to the
`individual need and tolerability.
`
`Duration of treatment
`The duration of treatment depends on clinical status and is left to the physician’s discretion. Should
`patients deteriorate on this treatment intravenous prostacyclin treatment should be considered.
`
`Special populations
`
`Hepatic impairment
`Iloprost elimination is reduced in patients with hepatic dysfunction (see section 5.2).
`
`To avoid undesired accumulation over the day, special caution has to be exercised with these patients
`during initial dose titration. Initially, doses of 2.5 microgram iloprost should be administered using
`Ventavis 10 microgram/ml with dosing intervals of 3-4 hours (corresponds to administration of max.
`6 times per day). Thereafter, dosing intervals may be shortened cautiously based on individual
`tolerability. If a dose up to 5 microgram iloprost is indicated, again dosing intervals of 3-4 hours
`should be chosen initially and shortened according to individual tolerability. An accumulation of
`iloprost following treatment over several days is not likely due to the overnight break in administration
`of the medicinal product.
`
`Renal impairment
`There is no need for dose adaptation in patients with a creatinine clearance >30 ml/min (as determined
`from serum creatinine using the Cockroft and Gault formula). Patients with a creatinine clearance of
`(cid:148)(cid:22)(cid:19) ml/min were not investigated in the clinical trials. Data with intravenously administered iloprost
`indicated that the elimination is reduced in patients with renal failure requiring dialysis. Therefore, the
`same dosing recommendations as in patients with hepatic impairment (see above) are to be applied.
`
`Paediatric population
`The safety and efficacy of Ventavis in children aged up to 18 years have not been established.
`No data from controlled clinical trials are available.
`
`Method of administration
`
`Ventavis is intended for inhalation use by nebulisation.
`
`To minimize accidental exposure it is recommended to keep the room well ventilated.
`
`The ready-to-use Ventavis nebuliser solution is administered with a suitable inhalation device
`(nebuliser) (see below and section 6.6).
`Patients stabilised on one nebuliser should not switch to another nebuliser without supervision by the
`treating physician as different nebulisers have been shown to produce aerosols with slightly different
`physical characteristics and delivery of the solution that may be faster (see section 5.2).
`
`(cid:120)
`
`Breelib
`
`Breelib is a small handheld, battery-powered, breath activated, vibrating mesh technology system.
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`Ventavis 10 microgram/ml (1 ml ampoule) and Ventavis 20 microgram/ml nebuliser solution
`
`Ventavis 10 microgram/ml nebuliser solution (1 ml ampoule) delivers 2.5 microgram and Ventavis 20
`microgram/ml nebuliser solution delivers 5 microgram at the mouthpiece of the Breelib nebuliser.
`
`At initiation of Ventavis treatment or if the patient is switched from an alternative device, the first
`inhalation should be made with 1 ml ampoule of Ventavis 10 microgram/ml (see section 4.4). If
`inhalation with Ventavis 10 microgram/ml is well tolerated, the dose should be increased by using
`Ventavis 20 microgram/ml. This dose should be maintained. In case of poor tolerability of Ventavis 20
`microgram/ml, the dose should be reduced by using 1 ml ampoule of Ventavis 10 microgram/ml (see
`section 4.4).
`
`The duration of an inhalation session with Breelib nebuliser is approximately 3 minutes, which reflects
`the higher delivery rate of the Breelib compared to other nebulisers.
`
`Patients initiating Ventavis treatment or switching from an alternative device to Breelib should be
`closely supervised by the treating physician to ensure that dose and speed of inhalation are well
`tolerated.
`
`When using the Breelib nebuliser please follow the instructions for use provided with the device.
`Fill the medication chamber with Ventavis immediately before use.
`
`(cid:120)
`
`I-Neb AAD
`
`The I-Neb AAD system is a portable, hand-held, vibrating mesh technology nebuliser system. This
`system generates droplets by ultrasound, which forces the solution through a mesh. The I-Neb AAD
`nebuliser has been shown to be suitable for the administration of Ventavis 10 microgram/ml (1 ml
`ampoule) and 20 microgram/ml nebuliser solution. The Mass Median Aerodynamic Diameter
`(MMAD) of the aerosol measured using I-Neb nebulising systems equipped with power level 10 disc
`was similar between Ventavis 20 microgram/ml (golden programme) and Ventavis 10 microgram/ml
`(purple programme) nebuliser solutions (i.e.: around 2 micrometres) but with faster delivery when
`using Ventavis 20 microgram/ml.
`
`The dose delivered by the I-Neb AAD system is controlled by the medication chamber in combination
`with a control disc. Each medication chamber is colour coded and has a corresponding colour coded
`control disc.
`
`Ventavis 10 microgram/ml nebuliser solution (1 ml ampoule)
`
`At initiation of Ventavis treatment with I-Neb system the first inhaled dose should be 2.5 microgram
`iloprost as delivered at the mouthpiece of the nebuliser using 1 ml ampoule of Ventavis
`10 microgram/ml. If this dose is well tolerated, dosing should be increased to 5 microgram iloprost
`using 1 ml ampoule of Ventavis 10 microgram/ml and maintained at that dose. In case of poor
`tolerability of the 5 microgram dose, the dose should be reduced to 2.5 microgram iloprost.
`
`This nebuliser monitors the breathing pattern to determine the aerosol pulse time required to deliver
`the pre-set dose of 2.5 or 5 microgram iloprost.
`For the 2.5 microgram dose of Ventavis 10 microgram/ml the medication chamber with the red
`coloured latch is used together with the red control disc.
`For the 5 microgram dose of Ventavis 10 microgram/ml the medication chamber with the purple
`coloured latch is used together with the purple control disc.
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`For each inhalation session with the I-Neb AAD, the content of one 1 ml ampoule of Ventavis
`10 microgram/ml, with two coloured rings (white - yellow), is transferred into the medication chamber
`immediately before use.
`
`Drug
`product
`
`Ampoule
`coloured ring
`
`Dosage
`
`I-Neb AAD
`
`Medication
`chamber latch
`
`Control
`disc
`
`Estimated
`inhalation
`time
`
`Ventavis
`10 mcg/ml
`
`1 ml ampoule
`white - yellow ring
`
`2.5 mcg
`5 mcg
`
`red
`purple
`
`red
`purple
`
`3.2 min
`6.5 min
`
`Ventavis 20 microgram/ml nebuliser solution
`
`Only patients who are maintained at the 5 microgram dose and who have repeatedly experienced
`extended inhalation times with Ventavis 10 microgram/ml, which could result in incomplete
`inhalation, may be considered suitable for switching to Ventavis 20 microgram/ml.
`
`Close supervision by the treating physician is necessary if switching from Ventavis 10 microgram/ml
`to Ventavis 20 microgram/ml to control the acute tolerance relating to faster delivery rate of iloprost
`with the double concentration.
`
`This nebuliser monitors the breathing pattern to determine the aerosol pulse time required to deliver
`the pre-set dose of 5 microgram iloprost.
`For the 5 microgram dose of Ventavis 20 microgram/ml the medication chamber with the gold
`coloured latch is used together with the gold control disc.
`
`For each inhalation session with the I-Neb AAD, the content of one 1 ml ampoule of Ventavis
`20 microgram/ml with two coloured rings (yellow - red), is transferred into the medication chamber
`immediately before use.
`
`Drug product
`
`Ampoule
`coloured rings
`
`Dosage
`
`I-Neb AAD
`
`Medication
`chamber latch
`
`Control disc
`
`Ventavis
`20 mcg/ml
`
`1 ml ampoule
`yellow - red ring
`
`5 mcg
`
`golden
`
`golden
`
`(cid:120)
`
`Venta-Neb
`
`Venta-Neb, a portable ultrasonic battery-powered nebuliser, has been shown to be suitable for the
`administration of Ventavis 10 microgram/ml nebuliser solution (2 ml ampoule). The measured
`MMAD of the aerosol droplets was 2.6 micrometres.
`
`At initiation of Ventavis treatment with Venta-Neb the first inhaled dose should be 2.5 microgram
`iloprost as delivered at the mouthpiece of the nebuliser using 2 ml ampoule of Ventavis
`10 microgram/ml. If this dose is well tolerated, dosing should be increased to 5 microgram iloprost
`using 2 ml ampoule of Ventavis 10 microgram/ml and maintained at that dose. In case of poor
`tolerability of the 5 microgram dose, the dose should be reduced to 2.5 microgram iloprost.
`
`For each inhalation session with the Venta-Neb, the content of one 2 ml ampoule of Ventavis
`10 microgram/ml with two coloured rings (white – pink) is transferred into the nebuliser medication
`chamber immediately before use.
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`Two programmes can be operated:
`P1 Programme 1: 5 microgram active substance on the mouth piece 25 inhalation cycles.
`P2 Programme 2: 2.5 microgram active substance on the mouth piece 10 inhalation cycles.
`The selection of the pre-set programme is made by the physician.
`
`Venta-Neb prompts the patient to inhale by an optical and an acoustic signal. It stops after the pre-set
`dose has been administered.
`To obtain the optimal droplet size for the administration of Ventavis 10 microgram/ml nebuliser
`solution the green baffle plate should be used. For details refer to the instruction manual of the Venta-
`Neb nebuliser.
`
`Drug product
`
`Ventavis 10 mcg/ml
`
`Ampoule
`coloured ring
`2 ml ampoule
`white - pink ring
`
`Dose of iloprost at
`mouthpiece
`2.5 mcg
`5 mcg
`
`Estimated inhalation
`time
`4 min
`8 min
`
`Other nebulising systems
`
`The efficacy and tolerability of inhaled iloprost when administered with other nebulising systems,
`which provide different nebulisation characteristics of iloprost solution, have not been established.
`
`4.3 Contraindications
`
`(cid:16)
`(cid:16)
`
`(cid:16)
`(cid:16)
`(cid:16)
`(cid:16)
`(cid:16)
`(cid:16)
`(cid:16)
`
`Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
`Conditions where the effects of Ventavis on platelets might increase the risk of haemorrhage
`(e.g. active peptic ulcers, trauma, intracranial haemorrhage).
`Severe coronary heart disease or unstable angina.
`Myocardial infarction within the last six months.
`Decompensated cardiac failure if not under close medical supervision.
`Severe arrhythmias.
`Cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last 3 months.
`Pulmonary hypertension due to venous occlusive disease.
`Congenital or acquired valvular defects with clinically relevant myocardial function disorders
`not related to pulmonary hypertension.
`
`4.4
`
`Special warnings and precautions for use
`
`The use of Ventavis is not recommended in patients with unstable pulmonary hypertension, with
`advanced right heart failure. In case of deterioration or worsening of right heart failure transfer to
`other medicinal products should be considered.
`
`Hypotension
`
`Blood pressure should be checked while initiating Ventavis. In patients with low systemic blood
`pressure and in patients with postural hypotension or receiving medicinal products known to reduce
`blood pressure levels, care should be taken to avoid further hypotension. Ventavis should not be
`initiated in patients with systolic blood pressure less than 85 mmHg.
`Physicians should be alerted to the presence of concomitant conditions or medicinal products that
`might increase the risk of hypotension and syncope (see section 4.5).
`
`Syncope
`
`The pulmonary vasodilatory effect of inhaled iloprost is of short duration (one to two hours).
`Syncope is a common symptom of the disease itself and can also occur under therapy. Patients who
`experience syncope in association with pulmonary hypertension should avoid any exceptional
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`straining, for example during physical exertion. Before physical exertion it might be useful to inhale.
`The increased occurrence of syncope can reflect therapeutic gaps, insufficient effectiveness and/or
`deterioration of the disease. The need to adapt and/or change the therapy should be considered (see
`section 4.8).
`
`Patients with diseases of the respiratory tract
`
`Ventavis inhalation might entail the risk of inducing bronchospasm, especially in patients with
`bronchial hyperactivity (see section 4.8). Moreover, the benefit of Ventavis has not been established in
`patients with concomitant Chronic Obstructive Pulmonary Disease (COPD) and severe asthma.
`Patients with concomitant acute pulmonary infections, COPD and severe asthma should be carefully
`monitored.
`
`Pulmonary veno-occlusive disease
`
`Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary
`veno-occlusive disease. Should signs of pulmonary oedema occur, the possibility of associated
`pulmonary veno-occlusive disease should be considered and treatment with Ventavis should be
`discontinued.
`
`Interruption of therapy
`
`In case of interruption of Ventavis therapy, the risk of rebound effect is not formally excluded. Careful
`monitoring of the patient should be performed when inhaled iloprost therapy is stopped and an
`alternative treatment should be considered in critically ill patients.
`
`Renal or hepatic impairment
`
`Data with intravenously administered iloprost indicated that the elimination is reduced in patients with
`hepatic dysfunction and in patients with renal failure requiring dialysis (see section 5.2). A cautious
`initial dose titration using dosing intervals of 3-4 hours is recommended (see section 4.2).
`
`Serum glucose levels
`
`Prolonged oral treatment with iloprost clathrate in dogs up to one year was associated with slightly
`increased fasted serum glucose levels. It cannot be excluded that this is also relevant to humans on
`prolonged Ventavis therapy.
`
`Undesirable exposure to Ventavis
`
`To minimise accidental exposure, it is recommended to use Ventavis with nebulisers with inhalation-
`triggered systems (such as Breelib or I-Neb), and to keep the room well ventilated.
`Newborns, infants and pregnant women should not be subjected to Ventavis in the room air.
`
`Skin and eye contact, oral ingestion
`
`Ventavis nebuliser solution should not come into contact with skin and eyes; oral ingestion of
`Ventavis solution should be avoided. During nebulisation sessions a facial mask must be avoided and
`only a mouthpiece should be used.
`
`Ventavis contains ethanol
`
`Ventavis 10 microgram/ml contains 0.81 mg alcohol (ethanol) in each ml which is equivalent to
`0.081% (w/v). The amount of 0.81 mg of alcohol in 1 ml of this medicine is equivalent to less than
`1 ml beer or wine.
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`Ventavis 20 microgram/ml contains 1.62 mg alcohol (ethanol) in each ml which is equivalent to
`0.162% (w/v). The amount of 1.62 mg of alcohol in 1 ml of this medicine is equivalent to less than
`1 ml beer or wine.
`
`The small amount of alcohol in this medicine will not have any noticeable effects.
`
`Switching to the Breelib nebuliser
`
`Limited data are available on the use of the Breelib nebuliser. For patients being switched from an
`alternative device to the Breelib nebuliser the first inhalation should be made with Ventavis
`10 microgram/ml (1ml ampoule) delivering 2.5 microgram iloprost at the mouthpiece and under close
`medical supervision to ensure that the faster inhalation provided by Breelib is well tolerated. First
`dosing with 2.5 microgram should be done even if patients had already been stable on 5 microgram
`inhaled with an alternative device (see section 4.2).
`
`4.5
`
`Interaction with other medicinal products and other forms of interaction
`
`Iloprost may increase the effects of vasodilatators and antihypertensive agents and then favour the risk
`of hypotension (see section 4.4). Caution is recommended in case of co-administration of Ventavis
`with other antihypertensive or vasodilatating agents as dose adjustment might be required.
`
`(cid:120)
`
`Since iloprost inhibits platelet function its use with the following substances may enhance iloprost-
`mediated platelet inhibition, thereby increasing the risk of bleeding:
`anticoagulants, such as
`(cid:120)
`-
`heparin,
`-
`oral anticoagulants (either coumarin-type or direct),
`or other inhibitors of platelet aggregation, such as
`-
`acetylsalicylic acid,
`-
`non-steroidal anti-inflammatory medicinal products,
`-
`non-selective phosphodiesterase inhibitors like pentoxifylline,
`-
`selective phosphodiesterase 3 (PDE3) inhibitors like cilostazol or anagrelide,
`-
`ticlopidine,
`-
`clopidogrel,
`-
`glycoprotein IIb/IIIa antagonists, like
`o
`abciximab,
`o
`eptifibatide,
`o
`tirofiban,
`defibrotide.
`
`-
`
`A careful monitoring of the patients taking anticoagulants or other inhibitors of platelet aggregation
`according to common medical practice is recommended.
`
`Intravenous infusion of iloprost has no effect either on the pharmacokinetics of multiple oral doses of
`digoxin or on the pharmacokinetics of co-administered tissue plasminogen activator (t-PA) in patients.
`Although, clinical studies have not been conducted, in vitro studies investigating the inhibitory
`potential of iloprost on the activity of cytochrome P450 enzymes revealed that no relevant inhibition
`of drug metabolism via these enzymes by iloprost is to be expected.
`
`4.6
`
`Fertility, pregnancy and lactation
`
`Women of childbearing potential
`
`Women of childbearing potential should use effective contraceptive measures during treatment with
`Ventavis.
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`Pregnancy
`
`Women with pulmonary hypertension (PH) should avoid pregnancy as it may lead to life-threatening
`exacerbation of the disease.
`Animal studies have shown reproductive effects (see section 5.3).
`There is a limited amount of data from the use of iloprost in pregnant women. If a pregnancy occurs,
`taking into account the potential maternal benefit, the use of Ventavis during pregnancy may be
`considered, only following careful benefit-risk evaluation, in those women who choose to continue
`their pregnancy, despite the known risks of pulmonary hypertension during pregnancy.
`
`Breast-feeding
`
`It is not known whether iloprost/metabolites are excreted in human breast milk. Very low levels of
`iloprost into milk were observed in rats (see section 5.3). A potential risk to the breast-feeding child
`cannot be excluded and it is preferable to avoid breast-feeding during Ventavis therapy.
`
`Fertility
`
`Animal studies have not shown harmful effect of iloprost on fertility.
`
`4.7 Effects on ability to drive and use machines
`
`Ventavis has major influence on the ability to drive and use machines for patients experiencing
`hypotensive symptoms such as dizziness.
`Care should be exercised during initiation of therapy until any effects on the individual have been
`determined.
`
`4.8 Undesirable effects
`
`Summary of the safety profile
`
`In addition to local effects resulting from administration of iloprost by inhalation such as cough,
`adverse reactions with iloprost are related to the pharmacological properties of prostacyclins.
`
`The most frequently observed adverse reactions ((cid:116) 20 %) in clinical trials include vasodilatation
`(including hypotension), headache and cough. The most serious adverse reactions were hypotension,
`bleeding events, and bronchospasm.
`
`Tabulated list of adverse reactions
`
`The adverse reactions reported below are based on pooled clinical trial data from phase II and III
`clinical trials involving 131 patients taking the medicinal product and on data from post-marketing
`surveillance. The frequencies of adverse reactions (cid:68)(cid:85)(cid:72)(cid:3)(cid:71)(cid:72)(cid:73)(cid:76)(cid:81)(cid:72)(cid:71)(cid:3)(cid:68)(cid:86)(cid:3)(cid:89)(cid:72)(cid:85)(cid:92)(cid:3)(cid:70)(cid:82)(cid:80)(cid:80)(cid:82)(cid:81)(cid:3)(cid:11)(cid:149)(cid:20)(cid:18)(cid:20)(cid:19)(cid:12)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:70)(cid:82)(cid:80)(cid:80)(cid:82)(cid:81)(cid:3)
`(cid:11)(cid:149)(cid:20)(cid:18)(cid:20)(cid:19)(cid:19)(cid:3)(cid:87)(cid:82)(cid:3)(cid:31)(cid:20)(cid:18)(cid:20)(cid:19)(cid:12)(cid:17)(cid:3)(cid:55)(cid:75)(cid:72)(cid:3)adverse reactions identified only during post-marketing surveillance, and for
`which a frequency could not be estimated from clinical trial data, are listed under "Frequency not
`known".
`
`Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
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`Not known (cannot
`be estimated from
`the available data)
`
`Thrombocytopenia
`
`Hypersensitivity
`
`Bronchospasm* (see
`section 4.4) /
`Wheezing
`
`Dysgeusia
`
`System organ class
`(MedDRA)
`
`Very common
`((cid:116)(cid:116)1/10)
`
`Common
`((cid:116)1/100 to <1/10)
`
`Blood and lymphatic system
`disorders
`Immune system disorders
`Nervous system disorders
`Cardiac disorders
`
`Vascular disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Bleeding events*§
`
`Headache
`
`Vasodilatation
`Flushing
`
`Chest discomfort /
`chest pain
`Cough
`
`Gastrointestinal disorders
`
`Nausea
`
`Skin and subcutaneous
`tissue disorders
`Musculoskeletal and
`connective tissue disorders
`
`Pain in jaw/trismus
`
`General disorders and
`administration site condition
`* Life-threatening and/or fatal cases have been reported.
`§ see section “Description of selected adverse reactions”
`
`Peripheral oedema§
`
`Description of selected adverse reactions
`
`Dizziness
`Tachycardia
`Palpitations
`Syncope§ (see
`section 4.4)
`Hypotension*
`Dyspnoea
`Pharyngolaryngeal
`pain
`Throat irritation
`Diarrhoea
`Vomiting
`Mouth and tongue
`irritation including
`pain
`Rash
`
`Bleeding events (mostly epistaxis and haemoptysis) were very common as expected in this patient
`population with a high proportion of patients taking anticoagulant co-medication. The risk of bleeding
`may be increased in patients when potential inhibitors of platelet aggregation or anticoagulants are
`given concomitantly (see section 4.5). Fatal cases included cerebral and intracranial haemorrhage.
`
`Syncope is a common symptom of the disease itself, but can also occur under therapy. The increased
`occurrence of syncope can be related to the deterioration of the disease or insufficient effectiveness of
`the product (see section 4.4).
`
`In clinical trials peripheral oedema was reported in 12.2% of patients on iloprost and 16.2% of patients
`on placebo. Peripheral oedema is a very common symptom of the disease itself, but can also occur
`under therapy. The occurrence of peripheral oedema can be related to the deterioration of the disease
`or insufficient effectiveness of the product.
`
`Reporting of suspected adverse reactions
`
`Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
`allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
`professionals are asked to report any suspected adverse reactions via the national reporting system
`listed in Appendix V.
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`4.9 Overdose
`
`Symptoms
`
`Cases of overdose were reported. Symptoms of overdoses are mainly related to the vasodilatory effect
`of iloprost. Frequently observed symptoms following overdose are dizziness, headache, flushing,
`nausea, jaw pain or back pain. Hypotension, an increase of blood pressure, bradycardia or tachycardia,
`vomiting, diarrhoea and limb pain might also be possible.
`
`Management
`
`A specific antidote is not known. Interruption of the inhalation session, monitoring and symptomatic
`measures are recommended.
`
`5.
`
`PHARMACOLOGICAL PROPERTIES
`
`5.1
`
`Pharmacodynamic properties
`
`Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin,
`ATC code: B01AC11
`
`Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue. The following
`pharmacological effects have been observed in vitro:
`Inhibition of platelet aggregation, platelet adhesion and release reaction
`(cid:120)
`Dilatation of arterioles and venules
`(cid:120)
`Increase of capillary density and reduction of increased vascular permeability caused by
`(cid:120)
`mediators such as serotonin or histamine in the microcirculation
`Stimulation of endogenous fibrinolytic potential
`
`(cid:120)
`
`The pharmacological effects after inhalation of Ventavis are:
`
`Direct vasodilatation of the pulmonary arterial bed occur with consecutive significant improvement of
`pulmonary artery pressure, pulmonary vascular resistance and cardiac output as well as mixed venous
`oxygen saturation.
`
`In a small, randomised, 12-week double-blinded, placebo-controlled study (the STEP trial), 34 patients
`treated with bosentan 125 mg twice per day for at least 16 weeks who were in stable haemodynamic
`conditions before enrolment, tolerated the addition of inhaled iloprost at the concentration of 10
`microgram/ml (up to 5 microgram 6 to 9 times per day during waking hours). The mean daily inhaled
`dose was 27 microgram and the mean number of inhalations per day was 5.6. The acute adverse
`effects in patients receiving concomitant bosentan and iloprost were consistent with those observed in
`the larger experience of the phase 3 study in patients receiving only iloprost. No reliable conclusion
`could be drawn on efficacy of the association as the sample size was limited and the study was of short
`duration.
`
`No clinical trial data are available comparing directly in intra-patient observations the acute
`haemodynamic response after intravenous to that after inhaled iloprost. The haemodynamics observed
`suggest an acute response with preferential effect of inhaled treatment on the pulmonary vessels. The
`pulmonary vasodilatory effect of each single inhalation levels off within one to two hours.
`
`However, the predictive value of these acute haemodynamic data are considered to be of limited value
`as acute response does not in all cases correlate with long-term benefit of treatment with inhaled
`iloprost.
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`Efficacy in adult patients with pulmonary hypertension
`
`A randomised, double-blind, multi-centre, placebo-controlled phase III trial (study RRA02997) has
`been conducted in 203 adult patients (inhaled iloprost at the concentration of 10 microgram/ml:
`n = 101; placebo n = 102) with stable pulmonary hypertension. Inhaled iloprost (or placebo) was
`added to patients' current therapy, which could include a combination of anticoagulants, vasodilators
`(e.g. calcium channel blockers), diuretics, oxygen, and digitalis, but not PGI2 (prostacyclin or its
`analogues). 108 of the patients included were diagnosed with primary pulmonary hypertension, 95
`were diagnosed with secondary pulmonary hypertension of which 56 were associated with chronic
`thromboembolic disease, 34 with connective tissue disease (including CREST and scleroderma) and 4
`were considered appetite suppressant medicinal product related. The baseline 6-minute walk test
`values reflected a moderate exercise limitation: in the iloprost group the mean was 332 metres (median
`value: 340 metres) and in the placebo group the mean was 315 metres (median value: 321 metres). In
`the iloprost group, the median daily inhaled dose was 30 microgram (range 12.5 to
`45 microgram/day). The primary efficacy endpoint defined for this study, was a combined response
`criterion consisting of improvement in exercise capacity (6-minute walk test) at 12 weeks by at least
`10% versus baseline, and improvement by at least one NYHA class at 12 weeks versus baseline, and
`no deterioration of pulmonary hypertension or death at any time before 12 weeks. The rate of
`responders to iloprost was 16.8% (17/101) and the rate of responders in the placebo group was 4.9%
`(5/102) (p = 0.007).
`
`In the iloprost group, the mean change from baseline after 12 weeks of treatment in the 6-minute
`walking distance was an increase of 22 metres (-3.3 metres in the placebo group, no data imputation
`for death or missing values).
`
`In the iloprost group the NYHA class was improved in 26% of patients (placebo: 15%) (p = 0.032),
`unchanged in 67.7% of patients (placebo: 76%) and deteriorated in 6.3% of patients (placebo: 9%).
`Invasive haemodynamic parameters were assessed at baseline and after 12 weeks treatment.
`
`A subgroup analysis showed that no treatment effect was observed as compared to placebo on the
`6-minute walk test in the subgroup of patients with secondary pulmonary hypertension.
`A mean increase in the 6-minute walk test of 44.7 metres from a baseline mean value of 329 metres
`vs. a change of -7.4 metres from a baseline mean value of 324 metres in the placebo group (no data
`imputation for death or missing values) was observed in the subgroup of 49 patients with primary
`pulmonary hypertension receiving treatment of inhaled iloprost for 12 weeks (46 patients in the
`placebo group).
`
`Paediatric population
`
`No study has been performed with Ventavis in children with pulmonary hypertension.
`
`5.2
`
`Pharmacokinetic properties
`
`Absorption
`
`When iloprost at the concentration of 10 microgram/ml is administered via inhalation in patients with
`pulmonary hypertension or healthy volunteers (iloprost dose at the mouthpiece: 5 microgram:
`inhalation time in between 4.6 – 10.6 min), mean peak serum concentrations of about 100 to
`200 picogram/ml were observed at the end of inhalation session. These concentrations decline with
`half-lives between approximately 5 and 25 minutes. Within 30 minutes to 2 hours after the end of
`inhalation, iloprost is not detectable in the central compartment (limit of quantification
`25 picogram/ml).
`
`Distribution
`
`No studies performed following inhalation.
`
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`Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 l/kg in
`healthy subjects. Total plasma protein binding of iloprost is concentration-independent in the range of
`30 to 3,000 picogram/ml and amounts to approximately 60%, of which 75% is due to albumin binding.
`
`Biotransformation
`
`No studies to investigate the metabolism of iloprost were performed following inhalation of Ventavis.
`
`After intravenous administration, iloprost is extensively metabolised via ß-oxidation of the carboxyl
`side chain. No unchanged substance is eliminated. The main metabolite is tetranor-iloprost, which is
`found in the urine in free and conjugated form. Tetranor-iloprost is pharmacologically inactive as
`shown in animal experiments. Results of in vitro studies reveal that CYP 4