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`ANNEX I
`
`SUMMARY OF PRODUCT CHARACTERISTICS
`
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`1
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`1.
`
`Ventavis 10 microgram/ml nebuliser solution.
`
`
`2.
`
`NAME OF THE MEDICINAL PRODUCT
`
`QUALITATIVE AND QUANTITATIVE COMPOSITION
`
` 1
`
`PHARMACEUTICAL FORM
`
`CLINICAL PARTICULARS
`
` ml solution contains 10 micrograms iloprost (as iloprost trometamol). Each 2-ml ampoule contains
`20 micrograms iloprost (as iloprost trometamol).
`
`For excipients, see 6.1.
`
`
`3.
`
`Nebuliser solution.
`Clear, colourless solution.
`
`
`4.
`
`4.1 Therapeutic indications
`
`Treatment of patients with primary pulmonary hypertension, classified as NYHA functional class III,
`to improve exercise capacity and symptoms.
`
`4.2 Posology and method of administration
`
`Ventavis should only be initiated and monitored by a physician experienced in the treatment of
`pulmonary hypertension.
`
`Ventavis is intended for inhalation use by nebulisation.
`
`Adults
`
` •
`
`
`
`Dose per inhalation session:
`
`
`The recommended dose is 2.5 micrograms or 5.0 micrograms of inhaled iloprost (as delivered at the
`mouthpiece of the nebuliser) according to the individual need and tolerability.
`
`Two compressed air nebuliser systems, HaloLite and Prodose, have been shown to be suitable
`nebulisers for the administration of Ventavis. With both systems the mass median aerodynamic
`diameter of the aerosol droplet (MMAD) with iloprost was between 2.6 and 2.7 µm. For each
`inhalation session the content of one 2-ml ampoule of Ventavis will be transferred into the nebuliser
`medication chamber immediately before use. HaloLite and Prodose are dosimetric systems. They stop
`automatically after the pre-set dose has been delivered. The inhalation time depends on the patient’s
`breathing pattern.
`
`
`Device
`
`HaloLite
`
`Prodose
`
`
`
`
`
`
`Dose of iloprost at
`mouthpiece
`2.5 µg
`5 µg
`2.5 µg
`5 µg
`
`Estimated Inhalation time
`(frequency of 15 breaths per minute)
`4 to 5 min
`8 to 10 min
`4 to 5 min
`8 to 10 min
`
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`For a dose of 5 µg iloprost at mouthpiece it is recommended to complete two inhalation cycles with
`2.5 µg pre-set dose program with a filling of one 2-ml ampoule.
`
`In addition Venta-Neb, a portable ultrasonic battery-powered nebuliser, has been shown to be suitable
`for the administration of Ventavis. The measured MMAD of the aerosol droplets was 2.6 µm. For each
`inhalation session, the content of one 2-ml ampoule of Ventavis will be transferred into the nebuliser
`medication chamber immediately before use.
`
`Two programs can be operated:
`PI Program 1 : 5,0 µg active substance on the mouth piece 25 inhalation cycles.
`P2 Program 2 : 2,5 µg active substance on the mouth piece 10 inhalation cycles.
`The selection of the pre set program 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 the
`green baffle plate should be used. For details refer to the instruction manual of the Venta-Neb
`nebuliser.
`
`
`Device
`Venta-Neb
`
`Dose of iloprost at mouthpiece
`2.5 µg
`5 µg
`
`Estimated Inhalation time
`4 min
`8 min
`
`
`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.
`
` •
`
`
`
`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.
`
`Patients with 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 µg should be administered with dosing intervals of
`at least 3 hours (corresponds to administration of max. 6 times per day). Thereafter, dosing intervals
`may be shortened cautiously based on individual tolerability. If a further increase in the dose up to
`5.0 µg is indicated, again dosing intervals of at least 3 hours should be chosen initially and shortened
`according to individual tolerability. A further undesired accumulation of the medicinal product
`following treatment over several days is not likely due to the overnight break in administration of the
`medicinal product.
`
`Patients with 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.
`
`Children and adolescents (below 18 years of age)
`
`
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`Currently no experience in children and adolescents is available.
`
`4.3 Contraindications
`
`Hypersensitivity to iloprost or to any of the excipients.
`
`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.
`
`Pregnancy, lactation.
`
`4.4 Special warnings and special 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.
`
`The pulmonary vasodilatory effect of inhaled iloprost is of short duration (one to two hours). 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 occurrence of a nocturnal or exertional syncope reflects therapeutic gaps and/or insufficient
`efficiency, and the need to adapt and/or change the therapy should be considered (see section 4.8).
`
`The benefit of Ventavis has not been established in patients with chronic pulmonary bronchitis and
`severe asthma. Patients with acute pulmonary infections should be carefully monitored.
`
`In patients with low systemic blood pressure, care should be taken to avoid further hypotension.
`Ventavis should not be initiated in patients with systolic arterial hypotension less than 85 mmHg.
`
`Should signs of pulmonary oedema occur when inhaled iloprost is administered in patients with
`pulmonary hypertension, the possibility of associated pulmonary veno-occlusive disease should be
`considered. The treatment should be stopped.
`
`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.
`
`Iloprost 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 at least
`3 hours is recommended (see section 4.2).
`
`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 man on
`prolonged Ventavis therapy.
`
`
`
`
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`Interaction with other medicinal products and other forms of interaction
`
`
`
`To minimise accidental exposure, it is recommended to use Ventavis with nebulisers with inhalation-
`triggered systems (HaloLite/Prodose), and to keep the room well ventilated.
`
`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.
`
`4.5
`
`Iloprost may increase the effect of vasodilatators and antihypertensive agents.
`
`Iloprost can inhibit platelet function and its use with anticoagulants (such as heparin, coumarin-type
`anticoagulants) or other inhibitors of platelet aggregation (such as acetylsalicylic acid, non-steroidal
`anti-inflammatory drugs, ticlopidine, clopidogrel and glycoprotein IIb/IIIa antagonists: abciximab,
`eptifibatide and tirofiban) may increase the risk of bleeding. A careful monitoring of the patients
`taking anticoagulants according to common medical practice is recommended. The concomitant use of
`other platelet inhibitors should be avoided in patients taking anticoagulants.
`
`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 have to be expected.
`
`4.6 Pregnancy and lactation
`
` •
`
`
`
`Pregnancy
`
`
`There are no adequate data from the use of Ventavis in pregnant women. Animal studies have shown
`reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ventavis is contra-
`indicated during pregnancy. Women of child-bearing potential should use effective contraceptive
`measures during treatment.
`
`Lactation
`
` •
`
`
`
`
`It is not known whether Ventavis enters the breast milk. The medicinal product must not be
`administered to breast feeding mothers (see section 4.3).
`
`4.7 Effects on ability to drive and use machines
`
`Care should be exercised during initiation of therapy until any effects on the individual have been
`determined. In patients experiencing hypotensive symptoms such as dizziness, the abilityto drive or
`operate machines may be affected.
`
`4.8 Undesirable effects
`
`In addition to local effects resulting from administration of iloprost by inhalation such as increased
`cough, adverse reactions with iloprost are related to the pharmacological properties of prostacyclins.
`
`The frequencies of the adverse reactions reported below (very common >10%, common >1 - 10%) are
`based on clinical trial data.
`
`Cardiovascular disorders
`
`Very common: vasodilatation, hypotension
`Common: syncope
`
`
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`Syncope is a common symptom of the disease itself, but can also occur under therapy. The increased
`occurrence of syncopes can be related to the deterioration of the disease or insufficient effectiveness of
`the product (see section 4.4).
`
`Respiratory, thoracic and mediastinal disorders
`
`Very common: increased cough
`
`Nervous system disorders
`
`Common: headache
`
`Musculoskeletal disorders
`
`Common: trismus
`
`Bleeding events (mostly haematoma) were common as expected in this patient population with a high
`proportion of patients taking anticoagulant co-medication. The frequency of bleeding events did not
`differ between iloprost and placebo-treated patients.
`
`4.9 Overdose
`
` •
`
`
`
`
`No case of overdose has been reported. Hypotensive/vasovagal reaction might be anticipated as well
`as headache, flushing, nausea, vomiting, and diarrhoea.
`
`Symptoms
`
`Therapy
`
` •
`
`
`
` A
`
` •
`
`
`
` •
`
`
`
` •
`
`
`
`PHARMACOLOGICAL PROPERTIES
`
` specific antidote is not known. Interruption of the inhalation session, monitoring and symptomatic
`measures are recommended.
`
`
`5.
`
`5.1 Pharmacodynamic properties
`
`Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01A C
`
`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
`
`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.
`
`
`
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`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: 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 drug related. The
`baseline 6-minute walk test values reflected a moderate exercise limitation: in the iloprost group the
`mean was 332 meters (median value: 340 meters) and in the placebo group the mean was 315 meters
`(median value: 321 meters). In the iloprost group, the median daily inhaled dose was 30 µg (range
`12.5 to 45 µg/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 meters (-3.3 meters 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.
`
` 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 meters from a baseline mean value of 329 meters vs.
`a change of -7.4 meters from a baseline mean value of 324 meters 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).
`
`No study has been performed with Ventavis in children with pulmonary hypertension.
`
`5.2 Pharmacokinetic properties
`
` A
`
` •
`
`
`
`Absorption
`
`
`When iloprost is administered via inhalation in patients with pulmonary hypertension (iloprost dose at
`the mouthpiece: 5 micrograms), peak serum levels of 100 to 200 picograms/ml were observed at the
`end of inhalation session. These levels decline with half-lives between approximately 5 and
`25 minutes. Within 30 minutes to 1 hour after the end of inhalation, iloprost is not detectable in the
`central compartment (limit of quantification 25 picograms/ml).
`
`
`
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`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 3000 picograms/ml and amounts to approximately 60 %, of which 75 % is due to albumin
`binding.
`
` •
`
`
`
`Metabolism
`
`
`No studies performed following inhalation.
`
`Iloprost is extensively metabolised principally 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 in 4 diastereoisomers. 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.
`
`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.
`
` A
`
` •
`
`
`
` mass-balance study was done using 3H-iloprost in healthy subjects. Following intravenous infusion,
`the recovery of total radioactivity is 81 %, and the respective recoveries in urine and faeces are 68 %
`and 12 %. The metabolites are eliminated from plasma and urine in 2 phases, for which half-lives of
`about 2 and 5 hours (plasma) and 2 and 18 hours (urine) have been calculated.
`
`
`Characteristics in patients
`
`
`Renal dysfunction:
`
`In a study with intravenous infusion of iloprost, patients with end-stage renal failure undergoing
`intermittent dialysis treatment are shown to have a significantly lower clearance
`(mean CL = 5 ± 2 ml/minute/kg) than that observed in patients with renal failure not undergoing
`intermittent dialysis treatment (mean CL = 18 ± 2 ml/minute/kg).
`
`Hepatic dysfunction:
`
`Because iloprost is extensively metabolised by the liver, the plasma levels of the active substance are
`influenced by changes in hepatic function. In an intravenous study, results were obtained involving 8
`patients suffering from liver cirrhosis. The mean clearance of iloprost is estimated to be
`10 ml/minute/kg.
`
`Age and gender:
`
`Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.
`
`5.3 Preclinical safety data
`
`
`
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` •
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`
`
`Systemic toxicity
`
`
`In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of
`intoxication or death (IV) at doses about two orders of magnitude above the intravenous therapeutic
`dose. Considering the high pharmacological potency of iloprost and the absolute doses required for
`therapeutic purposes the results obtained in acute toxicity studies do not indicate a risk of acute
`adverse effects in humans. As expected for a prostacyclin, iloprost produced haemodynamic effects
`(vasodilatation, reddening of skin, hypotension, inhibition of platelet function, respiratory distress)
`and general signs of intoxication such as apathy, gait disturbances, and postural changes.
`
`Continuous IV/SC infusion of iloprost up to 26 weeks in rodents and non-rodents did not cause any
`organ toxicity at dose levels which exceeded the human therapeutic systemic exposure between 14 and
`47 times (based on plasma levels). Only expected pharmacological effects like hypotension, reddening
`of skin, dyspnoea, increased intestinal motility were observed.
`
`Based on Cmax values in rats the systemic exposure in these parenteral studies was approximately
`3.5 times higher than the maximum achievable exposure after inhalation. This highest achievable dose
`of 48.7 micrograms/kg/day was also the “no observed adverse effect level” (NOAEL) as evaluated in
`inhalation toxicity studies in rats up to 26 weeks. Following inhalation the systemic exposure based on
`AUC values in rats exceeded the corresponding therapeutic exposure in human patients by
`approximately 13 times.
`
`
`Iloprost is not a gene mutagen in bacterial and mammalian cells in vitro and is not clastogenic in
`human lymphocytes up to cytotoxic concentrations and in the micronucleus test in vivo.
`
`No tumorigenic potential of iloprost could be demonstrated in tumorigenicity studies in rats and mice.
`
`Genotoxic potential, tumorigenicity
`
`Reproduction toxicology
`
`
`In embryo- and foetotoxicity studies in rats continuous intravenous administration of iloprost led to
`anomalies of single phalanges of the forepaws in a few foetuses/pups without dose dependence.
`
`These alterations are not considered as true teratogenic effects, but are most likely related to iloprost
`induced growth retardation in late organogenesis due to haemodynamic alterations in the
`foetoplacental unit. In comparable embryotoxicity studies in rabbits and monkeys no such digit
`anomalies or other gross-structural abnormalities were observed in the foetuses/pups up to the highest
`tested dose.
`
`In rats, passage of extremely low levels of iloprost into the milk was observed.
`
`Local tolerance, contact sensitising and antigenicity potential
`
` •
`
`
`
`
`In inhalation studies in rats, the administration of an iloprost formulation with a concentration of
`20 micrograms/ml up to 26 weeks did not cause any local irritation of the upper and lower respiratory
`tract.
`
` A
`
` dermal sensitisation (maximisation test) and an antigenicity study in guinea pigs showed no
`sensitising potential.
`
`
`6.
`
`6.1 List of excipients
`
`
`
`PHARMACEUTICAL PARTICULARS
`
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`
`trometamol
`ethanol 96 %
`sodium chloride
`hydrochloric acid for pH adjustment
`water for injections
`
`6.2
`
`In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
`products.
`
`6.3 Shelf life
`
`Incompatibilities
`
` 2
`
` years
`
`Instructions for use and handling
`
`
`6.4 Special precautions for storage
`
`No special precautions for storage.
`
`6.5 Nature and contents of container
`
`Ampoules of 3 ml, colourless, glass type I, containing 2 ml nebuliser solution.
`
`Packages containing 30, 100 and 300 ampoules.
`
`6.6
`
`For each inhalation session the contents of one opened ampoule of Ventavis has to be transferred into
`the nebuliser medication chamber immediately before use. After each inhalation session, any solution
`remaining in the nebuliser should be discarded.
`
`
`7. MARKETING AUTHORISATION HOLDER
`
`Schering AG, D-13342 Berlin, Germany
`
`
`8. MARKETING AUTHORISATION NUMBER(S)
`
`EU/1/03/255/001
`EU/1/03/255/002
`EU/1/03/255/003
`
`9.
`
`16. September 2003
`
`10. DATE OF REVISION OF THE TEXT
`
`{date}
`
`DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
`
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ANNEX II
`
`
`A. MANUFACTURING AUTHORISATION HOLDERS
`RESPONSIBLE FOR BATCH RELEASE
`
`B. CONDITIONS OF THE MARKETING AUTHORISATION
`
`C.
`
`SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE
`MARKETING AUTHORISATION HOLDER
`
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`
`A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
`RELEASE
`
`
`Name and address of the manufacturers responsible for batch release
`
`Schering AG, Müllerstraße 170 – 178, 13342 Berlin, Germany
`Berlimed. S.A., Poligono Industrial Santa Rosa s/n, 28806 Alcalá de Henarez, Madrid, Spain
`
`The printed package leaflet of the medicinal product must state the name and address of the
`manufacturer responsible for the release of the concerned batch.
`
`
`B. CONDITIONS OF THE MARKETING AUTHORISATION
`
` •
`
`
`
`CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
`THE MARKETING AUTHORISATION HOLDER
`
`
`Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
`Characteristics, section 4.2)
`
` •
`
`
`
`OTHER CONDITIONS
`
`
`The holder of this marketing authorisation must inform the European Commission about the marketing
`plans for the medicinal product authorised by this decision.
`
`
`C.
`
`SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
`AUTHORISATION HOLDER
`
`
`The Marketing Authorisation Holder shall complete the following programme of studies within the
`specified time frame, the results of which shall form the basis of the annual reassessment of the
`benefit/risk profile.
`
`Clinical aspects:
`
`
`
`In July 2004, the CHMP and MAH agreed on a protocol for an observational study 308120 to
`gather longer-term data on the safety and efficacy of Ventavis (iloprost). The first patient will be
`enrolled by April 2005 the latest. Progress reports will be provided together with the submission of
`the PSURs. A final study report will be provided within 6 months after last patient completed and
`forwarded for review by CHMP, estimated dated of 4Q 2009.
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`12
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`ANNEX III
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`LABELLING AND PACKAGE LEAFLET
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`13
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`A. LABELLING
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`14
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1009, p. 14 of 30
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`
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`PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO
`OUTER PACKAGING, ON THE IMMEDIATE PACKAGING
`
`OUTER CARTON / 30 AMPOULES
`
`1.
`
`Ventavis 10 microgram/ml
`Nebuliser solution
`Iloprost
`
`
`2.
`
`STATEMENT OF ACTIVE SUBSTANCE(S)
`
`NAME OF THE MEDICINAL PRODUCT
`
` 1
`
`LIST OF EXCIPIENTS
`
`PHARMACEUTICAL FORM AND CONTENTS
`
` ml solution contains 10 micrograms iloprost (as iloprost trometamol). Each 2-ml ampoule contains
`20 micrograms iloprost (as iloprost trometamol).
`
`
`3.
`
`trometamol, ethanol 96 %,
`sodium chloride, hydrochloric acid for pH adjustment,
`water for injections
`
`
`4.
`
`Nebuliser solution
`30 ampoules with 2 ml
`
`
`5. METHOD AND ROUTE(S) OF ADMINISTRATION
`
`Inhalation use
`Read the package leaflet before use
`
`
`6.
`
`SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
`OF THE REACH AND SIGHT OF CHILDREN
`
`
`Keep out of the reach and sight of children
`
`
`7.
`
`
`8.
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`EXP {MM/YYYY}
`
`
`
`OTHER SPECIAL WARNING(S), IF NECESSARY
`
`EXPIRY DATE
`
`
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`15
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1009, p. 15 of 30
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`

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`SPECIAL STORAGE CONDITIONS
`
`
`
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`9.
`
`There are no special storage instructions
`
`
`10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
`OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
`APPROPRIATE
`
`
`
`11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
`
`Schering AG, D-13342 Berlin, Germany
`
`
`12. MARKETING AUTHORISATION NUMBER(S)
`
`EU/1/03/255/001
`
`
`13. MANUFACTURER’S BATCH NUMBER
`
`Lot {number}
`
`
`14. GENERAL CLASSIFICATION FOR SUPPLY
`
`Medicinal product subject to medical prescription
`
`
`15.
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`INSTRUCTIONS ON USE
`
`
`
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`16
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1009, p. 16 of 30
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`

`

`
`
`PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO
`OUTER PACKAGING, ON THE IMMEDIATE PACKAGING
`
`OUTER CARTON / 100 AMPOULES
`
`1.
`
`Ventavis 10 microgram/ml
`Nebuliser solution
`Iloprost
`
`
`2.
`
`STATEMENT OF ACTIVE SUBSTANCE(S)
`
`NAME OF THE MEDICINAL PRODUCT
`
` 1
`
`LIST OF EXCIPIENTS
`
`PHARMACEUTICAL FORM AND CONTENTS
`
` ml solution contains 10 micrograms iloprost (as iloprost trometamol). Each 2-ml ampoule contains
`20 micrograms iloprost (as iloprost trometamol).
`
`
`3.
`
`trometamol, ethanol 96 %,
`sodium chloride, hydrochloric acid for pH adjustment,
`water for injections
`
`
`4.
`
`Nebuliser solution
`100 ampoules with 2 ml
`
`
`5. METHOD AND ROUTE(S) OF ADMINISTRATION
`
`Inhalation use
`Read the package leaflet before use
`
`
`6.
`
`SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
`OF THE REACH AND SIGHT OF CHILDREN
`
`
`Keep out of the reach and sight of children
`
`
`7.
`
`
`8.
`
`EXP {MM/YYYY}
`
`
`
`OTHER SPECIAL WARNING(S), IF NECESSARY
`
`EXPIRY DATE
`
`
`
`
`17
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1009, p. 17 of 30
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`

`

`SPECIAL STORAGE CONDITIONS
`
`
`
`
`9.
`
`There are no special storage instructions
`
`
`10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
`OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
`APPROPRIATE
`
`
`
`11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
`
`Schering AG, D-13342 Berlin, Germany
`
`
`12. MARKETING AUTHORISATION NUMBER(S)
`
`EU/1/03/255/002
`
`
`13. MANUFACTURER’S BATCH NUMBER
`
`Lot {number}
`
`
`14. GENERAL CLASSIFICATION FOR SUPPLY
`
`Medicinal product subject to medical prescription
`
`
`15.
`
`INSTRUCTIONS ON USE
`
`
`
`
`18
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1009, p. 18 of 30
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`

`

`
`
`PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO
`OUTER PACKAGING, ON THE IMMEDIATE PACKAGING
`
`OUTER CARTON / 300 AMPOULES
`
`1.
`
`Ventavis 10 microgram/ml
`Nebuliser solution
`Iloprost
`
`
`2.
`
`STATEMENT OF ACTIVE SUBSTANCE(S)
`
`NAME OF THE MEDICINAL PRODUCT
`
` 1
`
`LIST OF EXCIPIENTS
`
`PHARMACEUTICAL FORM AND CONTENTS
`
` ml solution contains 10 micrograms iloprost (as iloprost trometamol). Each 2-ml ampoule contains
`20 micrograms iloprost (as iloprost trometamol).
`
`
`3.
`
`trometamol, ethanol 96 %,
`sodium chloride, hydrochloric acid for pH adjustment,
`water for injections
`
`
`4.
`
`Nebuliser solution
`300 ampoules with 2 ml
`
`
`5. METHOD AND ROUTE(S) OF ADMINISTRATION
`
`Inhalation use
`Read the package leaflet before use
`
`
`6.
`
`SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
`OF THE REACH AND SIGHT OF CHILDREN
`
`
`Keep out of the reach and sight of children
`
`
`7.
`
`
`8.
`
`EXP {MM/YYYY}
`
`
`
`OTHER SPECIAL WARNING(S), IF NECESSARY
`
`EXPIRY DATE
`
`
`
`
`19
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1009, p. 19 of 30
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`

`

`SPECIAL STORAGE CONDITIONS
`
`
`
`
`9.
`
`There are no special storage instructions
`
`
`10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
`OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
`APPROPRIATE
`
`
`
`11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
`
`Schering AG, D-13342 Berlin, Germany
`
`
`12. MARKETING AUTHORISATION NUMBER(S)
`
`EU/1/03/255/003
`
`
`13. MANUFACTURER’S BATCH NUMBER
`
`Lot {number}
`
`
`14. GENERAL CLASSIFICATION FOR SUPPLY
`
`Medicinal product subject to medical prescription
`
`
`15.
`
`INSTRUCTIONS ON USE
`
`
`
`
`20
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1009, p. 20 of 30
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`

`

`
`
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`MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
`
`Ampoule
`
`
`1.
`
`Ventavis 10 microgram/ml
`Nebuliser solution
`Iloprost
`Inhalation use
`
`
`2. METHOD OF ADMINISTRATION
`
`Read the package leaflet before use.
`
`
`3.
`
`EXP {MM/YYYY}
`