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`Ventavis 10 microgram/ml nebuliser solution
`
`Last Updated on eMC 14-Dec-2016 View changes | Bayer plc Contact details
`
`1. Name of the medicinal product
`
`2. Qualitative and quantitative
`composition
`
`3. Pharmaceutical form
`
`4. Clinical particulars
`
`4.1 Therapeutic indications
`
`4.2 Posology and method of
`administration
`
`4.3 Contraindications
`
`4.4 Special warnings and
`precautions for use
`
`4.5 Interaction with other
`medicinal products and other
`forms of interaction
`
`4.6 Fertility, pregnancy and
`lactation
`
`4.7 Effects on ability to drive and
`use machines
`
`4.8 Undesirable effects
`
`4.9 Overdose
`
`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:
`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)
`For the full list of excipients, see section 6.1.
`
`5. Pharmacological properties
`
`3. Pharmaceutical form
`
`5.1 Pharmacodynamic properties
`
`5.2 Pharmacokinetic properties
`
`5.3 Preclinical safety data
`
`6. Pharmaceutical particulars
`
`6.1 List of excipients
`
`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
`6.2 Incompatibilities
`This site uses cookies. By continuing to browse the site you are agreeing to our policy on the use of cookies. Continue
`6.3 Shelf life
`4.1 Therapeutic indications
`
`Find out more here.
`
`6.4 Special precautions for
`storage
`
`6.5 Nature and contents of
`container
`
`6.6 Special precautions for
`disposal and other handling
`
`7. Marketing authorisation holder
`
`8. Marketing authorisation
`number(s)
`
`9. Date of first
`authorisation/renewal of the
`
`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
`
`Breelib
`
`I-Neb AAD
`
`Venta-Neb
`
`I-Neb AAD
`Breelib
`Ventavis 20 microgram/ml
`Ventavis should only be initiated and monitored by a physician experienced in the treatment of pulmonary hypertension.
`Posology
`Dose per inhalation session
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1036, p. 1 of 11
`
`

`

`authorisation
`
`10. Date of revision of the text
`
`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 ≤30 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).
`• Breelib
`Breelib is a small handheld, battery-powered, breath activated, vibrating mesh technology system.
`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.
`• 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
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1036, p. 2 of 11
`
`

`

`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.
`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.
`I-Neb AAD
`
`Drug product
`
`Ampoule
`coloured ring
`
`Ventavis 10
`mcg/ml
`
`1 ml ampoule white -
`yellow ring
`
`Dosage
`
`2.5 mcg
`
`5 mcg
`
`Estimated
`inhalation time
`
`Medication chamber
`latch
`
`Control disc
`
`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.
`I-Neb AAD
`
`Drug product
`
`Ampoule
`coloured rings
`
`Dosage
`
`Medication chamber
`latch
`
`Control disc
`
`Ventavis 20 mcg/ml
`
`1 ml ampoule yellow - red
`ring
`
`5 mcg
`
`golden
`
`golden
`
`• 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.
`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
`Ampoule
`Dose of iloprost at
`Estimated inhalation time
`mouthpiece
`coloured ring
`
`Ventavis 10 mcg/ml
`
`2 ml ampoule white -
`pink ring
`
`2.5 mcg
`5 mcg
`
`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
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1036, p. 3 of 11
`
`

`

`- 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 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
`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
`This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
`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
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1036, p. 4 of 11
`
`

`

`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.
`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
`- 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
`o 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
`
`Pregnancy
`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. Taking into account the potential maternal
`benefit, the use of Ventavis during pregnancy may be considered 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 (≥ 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
`are defined as very common (≥1/10) and common (≥1/100 to <1/10). The 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".
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1036, p. 5 of 11
`
`

`

`Within each frequency grouping, adverse reaction are presented in order of decreasing seriousness.
`System organ class
`Very common
`Common
`Not known (cannot be
`estimated from the
`(MedDRA)
`(≥1/10)
`(≥1/100 to <1/10)
`available data)
`
`Blood and lymphatic system
`disorders
`
`Immune system disorders
`
`Bleeding events*
`
`§
`
`Nervous system disorders
`
`Headache
`
`Dizziness
`
`Thrombocytopenia
`
`Hypersensitivity
`
`Cardiac disorders
`
`Vascular disorders
`
`Respiratory, thoracic and
`mediastinal disorders
`
`Vasodilatation
`Flushing
`
`Chest discomfort / chest
`pain
`Cough
`
`Gastrointestinal disorders
`
`Nausea
`
`Skin and subcutaneous tissue
`disorders
`
`Musculoskeletal and connective
`tissue disorders
`
`Pain in jaw/trismus
`
`Tachycardia, Palpitations
`
`§
`Syncope (see section
`4.4)
`Hypotension*
`
`Dyspnoea
`Pharyngolaryngeal pain
`Throat irritation
`
`Diarrhoea
`Vomiting
`Mouth and tongue
`irritation including pain
`
`Rash
`
`Bronchospasm* (see
`section 4.4) / Wheezing
`
`Dysgeusia
`
`§
`
`Peripheral oedema
`
`General disorders and
`administration site condition
`* Life-threatening and/or fatal cases have been reported.
`§ see section “Description of selected adverse reactions”
`Description of selected adverse reactions
`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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
`
`4.9 Overdose
`
`Symptoms
`In the case of an overdose hypotensive/vasovagal reaction might be anticipated as well as headache, flushing, nausea,
`vomiting, and diarrhoea. An increase of blood pressure, bradycardia or tachycardia and limb or back pain might 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
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1036, p. 6 of 11
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`

`

`• Dilatation of arterioles and venules
`• Increase of capillary density and reduction of increased vascular permeability caused by mediators such as serotonin or
`histamine in the microcirculation
`• Stimulation of endogenous fibrinolytic potential
`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.
`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.
`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 450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Further in vitro
`studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.
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`Elimination
`No studies performed following inhalation.
`In subjects with normal renal and hepatic function, the disposition of iloprost following intravenous infusion is characterised
`in most cases by a two-phase profile with mean half-lives of 3 to 5 minutes and 15 to 30 minutes. The total clearance of
`iloprost is about 20 ml/kg/min, which indicates extrahepatic contribution to the metabolism of iloprost.
`3
`A mass-balance study was done using H-iloprost in healthy subjects. Following intravenous infusion, the recovery of total
`radioactivity is 81 %, and the respectiv