`
`Page 3
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`Ventavis
`
`(iloprost) Inhalation Solution
`
`Rx Only
`
`DESCRIPTION
`
`Ventavis (iloprost) Inhalation Solution is a clear, colorless, sterile solution containing 10 mcg/mL
`iloprosl formulated for inhalation via the Prodose® AAD® (Adaptive Aerosol Delivery) System, a
`pulmonary drug delivery device. Each single-use glass ampule contains 2 mL (20 mcg) of the solution
`to be added to the Prodose AAD System medication chamber. Each mL of the aqueous solution
`contains 0.0] mg iloprost, 0.8] mg ethanol, 0.12] mg tromethamine, 9.0 mg sodium chloride, and
`approximately 0.51 mg hydrochloric acid (for pH adjustment to 8.1) in water for injection. The
`solution contains no preservatives.
`
`The chemical name for iloprosl is (E)-(3aS,4R,5R,6aS)—hexahydro-5-hydroxy-4—[(h)-(3S,4RS)-3-
`hydroxy—4-methyl-1-octen-6—ynyl]-A2(lm’A-pentalenevaleric acid. Iloprost consists of a mixture of the
`4R and 4S diastereomers at a ratio of approximately 53:47. Iloprost is an oily substance, which is
`soluble in methanol, ethanol, ethyl acetate, acetone and pH 7 buffer, sparingly soluble in buffer pH 9,
`and very slightly soluble in distilled water, buffer pH 3, and buffer pH 5.
`
`The molecular formula of iloprost is C32H3304. Its relative molecular weight is 360.49. The structural
`formula is shown below:
`
`COOH
`
`OH
`
`OH
`
`CLINICAL PHARMACOLOGY
`
`General
`
`Iloprost is a synthetic analogue of prostacyclin PGIL Iloprost dilates systemic and pulmonaty arterial
`vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of
`pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in
`dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer.
`
`Pharmaeokinetics
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`General
`
`In pharrnacokinetic studies in animals, there was no evidence of interconversion of the two
`diastereoisomers of iloprost. In human pharmacokinetic studies, the two diastereoisomers were not
`individually assayed.
`
`lloprost administered intravenously has linear pharrnacokinetics over the dose range of 1 to 3
`ngfkg/min. The half—life of iloprost is 20 to 30 minutes. Following inhalation of iloprost (5 mcg)
`patients with pulmonary hypertension have iloprost peak serum levels of approximately 150 pgx’mL.
`lloprost was generally not detectable in the plasma 30 minutes to 1 hour after inhalation.
`
`Absorption and Distribution
`
`The absolute bioavailability of inhaled iloprost has not been determined.
`
`Following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 Lfkg in
`healthy subjects. lloprost is appr0ximately 60% protein-bound, mainly to albumin, and this ratio is
`concentration-independent in the range of 30 to 3000 pg/mL.
`
`Metabolism and Excretion
`
`lloprost is metabolized principally via
`Clearance in normal subjects was appmximately 20 va’minfkg.
`B-OXidation of the carbOxyl side chain. The main metabolite is tetranor—iloprost, which is found in the
`urine in free and conjugated Form. In animal experiments, tetranor—iloprost was pharmacological ly
`inactive.
`
`In vitro studies reveal that cytochrome P450—dependent metabolism plays only a minor role in the
`biotransformation of iloprost.
`
`A mass-balance study using intravenously and orally administered |3H |-iloprost in healthy subjects
`(n=8) showed recovery of total radioactivity over 14 hours post-dose, was 81%, with 68% and 12%
`recoveries in urine and feces, respectively.
`
`Special Populations
`
`Liver Function Impairment
`
`Inhaled iloprost has not been evaluated in subjects with impaired hepatic function. However, in an
`intravenous iloprost study in patients with liver cirrhosis, the mean clearance in Child Pugh Class B
`subjects (n = 5) was approximately 10 mLfminfkg (half that of healthy subjects). Following oral
`administration, the mean AUCu_gh in Child Pugh Class B subjects (n= 3) was 1725 pg*hme compared
`to 117 pg*h.r’mL in normal subjects (n=4) receiving the same oral iloprost dose. In Child Pugh Class A
`subjects (n= 5), the mean AUC0-3h was 639 pg*hme. Although exposure increased with hepatic
`impairment, there was no effect on half-life.
`
`Renal Function Impairment
`
`Inhaled iloprost has not been evaluated in subjects with impaired renal function. However, in a study
`with intravenous infusion of iloprost in patients with end-stage renal failure requiring intermittent
`dialysis treatment (n=7), the mean AUCMh was 230 pg*hi’n1L compared to 54 pg*hme in patients
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`with renal failure (n=8) not requiring intermittent dialysis and 48 pg*hme in normals. The half-life
`was similar in both groups. The effect of dialysis on iloprost exposure has not been evaluated.
`
`Clinical Trials
`
`A randomized, double-blind, multi-center, placebo-controlled trial was conducted in 203 adult patients
`(inhaled iloprost: n=101; placebo: n=102) with NYHA Class III or IV pulmonary arterial hypertension
`(PAH, WHO Group I; idiopathic in 53%, associated with connective tissue disease, including CREST
`and scleroderma, in 17%, or associated with anorexigen use in 2%) or pulmonary hypertension related
`to chronic thromboembolic disease (WHO Group IV; 28%). Inhaled iloprost (or placebo) was added to
`patients‘ current therapy, which could have included anticoagulants, vasodilators (e. g. calcium channel
`blockers), diuretics, oxygen, and digitalis, but not PGIg (prostacyclin or its analogues) or endothelin
`receptor antagonists. Patients received 2.5 or 5.0 mcg of iloprost by repeated inhalations 6 to 9 times
`per day during waking hours. The mean age of the entire study population was 52 years and 68% of the
`patients were female. The majority of patients (59%) were NYHA Class 111. The baseline 6-minute
`walk test values reflected a moderate exercise limitation (the mean was 332 meters for the iloprost
`group and 315 meters for the placebo group). In the iloprost group, the median daily inhaled dose was
`30 mcg (range of 12.5 to 45 mcg/day). The mean number of inhalations per day was 7.3. Ninety
`percent of patients in the iloprost group never inhaled study medication during the nighttime.
`
`The primary efficacy endpoint was clinical response at 12 weeks, a composite endpoint defined by: a)
`improvement in exercise capacity (6-minute walk test) by at least 10% versus baseline evaluated 30
`minutes after dosing, b) improvement by at least one NYHA class versus baseline, and c) no death or
`deterioration of pulmonary hypertension. Deterioration required two or more of the following criteria:
`1) refractory systolic blood pressure < 85 mmHg, 2) worsening of right heart failure with cardiac
`edema, ascites, or pleural effusion despite adequate background therapy, 3) rapidly progressive
`cardiogenic hepatic failure (e. g. leading to an increase of GOT or GPT to > 100 UfL, or total bilirubin
`3 5 mg/dL), 4) rapidly progressive cardiogenic renal failure (e.g. decrease of estimated creatinine
`clearance to 5 50% of baseline), 5) decrease in 6-minute walking distance by 2 30% of baseline value,
`6) new long-term need for i.v. catecholamines or diuretics, 7") cardiac index _<_ 1.3 Uminfmz, 8) CVP 3
`_ 22 mran despite adequate diuretic therapy, and 9) SVO; _<_ 45% despite nasal 02 therapy.
`
`Although effectiveness was seen in the full population (response rates for the primary composite
`endpoint of 17% and 5%; p=0.007), there was inadequate evidence of benefit in patients with
`pulmonary hypertension associated with chronic thromboembolic disease (WHO Group IV); the
`results presented are therefore those related to patients with PAH (WHO Group 1). The response rate
`for the primary effrcacy endpoint among PAH patients was 19% for the iloprost group, compared with
`4% for the placebo group (p=0.003 3). All three components of the composite endpoint favored iloprost
`(Figure 1).
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`after Inhalation
`
`Death or
`Clinical
`Worsening
`
`Composite
`Clinical
`Endpoint
`
`6-Minute Walk
`10% Increase
`at 30 Minutes
`
`NYHA Class
`Improvement
`
`The absolute change in 6-minute walk distance (Figure 2) measured (using all available data and no
`imputation) 30 minutes after inhalation among patients with PAH was greater in the iloprost group
`compared to the placebo group at all time points. At Week 12, the placebo-corrected difference was 40
`meters (p<0.01). When walk distance was measured immediately prior to inhalation, the improvement
`compared to placebo was approximately 60% of the effect seen at 30 minutes after inhalation.
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`Figure 2 — Change (Mean :I: SEM) in 6-Minute Walk Distance 30 Minutes post Inhalation in PAH
`Patients (WHO Group I).
`
`+ h D
`
`+ M D
`
`+0
`
`lb 0
`
`.L D
`
`I
`
`I
`
`+|loprosl
`+Placebo
`
`a:
`.E
`Em
`a
`.9
`Hi>
`»
`
`oc
`
`c Eo
`
`Baseline
`available data.
`
`u:..
`2oW
`.o
`«I
`
`hoi
`
`:
`«I
`
`oE
`
`The effect of Ventavis in various subgroups is shown in Table 1.
`
`Table 1 Treatment Effects by Subgroup among PAH Patients (WHO Group 1)
`
`6—Mi11utc Walk”c
`Composite Clinical Endpoint
`Vcnlavis
`Placebo
`
`n Placebo Ventavis n
`
`
`flgmean i SD) {mean :t SD)
`
`
`3li76
`65
`3179
`3 (4%)
`All Subjects
`68
`13 (19%)
`78
`with PAH
`
`NYIIA Ill
`
`NYIIA IV
`
`Male
`
`Female
`
`7" (18%)
`
`6 (21%)
`
`-
`
`5 (22%)
`
`8 (18%)
`
`2 (4%)
`
`l (3%)
`
`0 (0%)
`
`3 (6%)
`
`2 (5%)
`6 (15%)
`Age 3 55
`
`1 (3%)
`Age > 55
`7 {26%)
`
`* Change from baseline to 12 Weeks with measurement 30 minutes after dosing, based on all
`
`Treatment-related effects on hemodynamic measures (eg. PVR, mPAP, CO, SVOg) have not been
`demonstrated.
`
`INDICATIONS AN D USAGE
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`Ventavis is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients
`with NYHA Class III or IV symptoms. In controlled trials, it improved a composite endpoint
`consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration (see CLINICAL
`PHARMACOLOGY, Clinical Trials). Ventavis has not been adequately studied with concomitant
`use of other approved therapies for pulmonary arterial hypertension.
`
`CONTRAINDICATIONS
`
`There are no known contraindications.
`
`WARNINGS
`
`Ventavis is intended for inhalation administration only via the ProdoseIn AADE System, a pulmonary
`drug delivery device (See DOSAGE AND ADMINISTRATION). It has not been studied with any
`other nebulizers.
`
`In patients
`Because of the risk of syncope, vital signs should be monitored while initiating Ventavis.
`with low systemic blood pressure, 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 alert
`to the presence of concomitant conditions or drugs that might increase the risk of syncope. Syncope
`can also occur in association with pulmonary arterial hypertension, particularly in association with
`physical exertion. The occurrence of exertional syncope may reflect a therapeutic gap or insufficient
`efficacy, and the need to adjust dose or change therapy should be considered.
`
`Should signs of pulmonary edema occur when inhaled iloprost is administered in patients with
`pulmonary hypertension, the treatment should be stopped immediately. This may be a sign of
`pulmonary venous hypertension.
`
`PRECAUTIONS
`
`General
`
`Ventavis solution should not be allowed to come into contact with the skin or eyes; oral ingestion of
`Ventavis solution should be avoided.
`
`Direct mixing of Ventavis with other medications in the Prodose AAD System has not been evaluated.
`
`Ventavis has not been evaluated in patients with chronic obstructive pulmonary disease (COPD),
`severe asthma, or with acute pulmonary infections.
`
`Information for Patients
`
`Patients receiving Ventavis should be advised to use the drug only as prescribed with the Prodose
`AAD System, a pulmonary drug delivery device, following the manufacturer’s instructions (see
`DOSAGE AND ADMINISTRATION). Patients should be trained in proper administration
`techniques including dosing frequency, ampule dispensing, Prodose AAD System operation, and
`equipment cleaning.
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`Patients should be advised that they may have a fall in blood pressure with Ventavis, so they may
`become dizzy or even faint. They should stand up slowly when they get out of a chair or bed. If
`fainting gets worse, patients should consult their physicians about dose adjustment.
`
`Patients should be advised that Ventavis should be inhaled at intervals of not less than 2 hours and that
`
`the acute benefits of Ventavis may not last 2 hours.
`
`Drug Interactions
`
`In studies in normal volunteers, there was no phannacodynamic interaction between intravenous
`iloprost and either nifedipine, diltiaxem, or captopril. However, iloprost has the potential to increase
`the hypotensive effect of vasodilators and antihypertensive agents. Since iloprost inhibits platelet
`function, there is a potential for increased risk of bleeding, particularly in patients maintained on
`anticoagulants. During clinical trials, iloprost was used concurrently with anticoagulants, diuretics,
`cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-
`inflammatories, corticosteroids, and other medications. Intravenous infilsion of iloprost had no effect
`on the pharmacokinetics of digoxin. Acetylsalicylic acid did not alter the clearance (pharrnacokinetics)
`of iloprost. Although clinical studies have not been conducted, in vitro studies of iloprost indicate that
`no relevant inhibition of cytochrome P450 drug metabolism would be expected.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`lloprost was not mutagenic in bacterial and mammalian cells in the presence or absence of extrinsic
`metabolic activation.
`lloprost did not cause chromosomal aberrations in vitro in human lymphocytes
`and was not clastogenic in vivo in NMRUSPF mice. There was no evidence of a tumorigenic effect of
`iloprost clathrate (13% iloprost by weight) in Sprague-Dawley rats dosed orally for up to 8 months at
`doses of up to 125 mgfkgfday (Cmax of 45 ng/mL serum), followed by 16 months at 100 mgfkg/day,
`or in Crl:CD-l®(ICR)BR albino mice dosed orally for up to 24 months at doses of up to 125
`mg/kg/day (Cmax of 156 ngme serum). The recommended clinical dosage regimen for iloprost (5
`mcg) affords a serum Cmax of 0, l 6 ng/mL. Fertility of males or females was not impaired in Han-
`Wistar rats at intravenous doses up to 1 mg/kg/day.
`
`Pregnancy
`
`Pregnancy Categogy C. In developmental 10xicity studies in pregnant Han-Wistar rats, continuous
`intravenous administration of iloprost at a dosage of 0.01 mg/kg daily (serum levels not available) led
`to shortened digits of the thoracic extremity in fetuses and pups. In comparable studies in pregnant
`Sprague-Dawley rats which received iloprost clathrate (13% iloprost by weight) orally at dosages of up
`to 50 mg/kg/day (Cmax of 90 ng/mL), in pregnant rabbits at intravenous dosages of up to 0.5
`mg/kg/day (Cmax of 86 ng/mL), and in pregnant monkeys at dosages of up to 0.04 mg/kg/day (serum
`levels of 1 ng/mL), no such digital anomalies or other gross-structural abnormalities were observed in
`the fetusesfpups. However, in gravid Sprague-Dawley rats, iloprost clathrate (13% iloprost)
`significantly increased the number of non-viable fetuses at a maternally toxic oral dosage of 250
`mgfkg/day and in Han-Wistar rats was found to be embryolethal in 15 of 44 litters at an intravenous
`dosage of 1 mg/kg/day. There are no adequate and well-controlled studies in pregnant women.
`Ventavis should be used during pregnancy only if the potential benefitjustifies the potential risk to the
`fetus.
`
`Nursing Mothers
`
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`It is not known whether Ventavis is excreted in human milk. In studies with Han-Wistar rats, higher
`mortality was observed in pups of lactating dams receiving iloprost intravenously at 1 mg/kg daily. In
`Sprague-Dawley rats, higher mortality was also observed in nursing pups at a maternally toxic oral
`dose of 250 mg/kgfday of iloprost clathrate (13% iloprost by weight). It is not known whether this
`drug is excreted in human milk. Because many drugs are excreted in human milk and because of the
`potential for serious adverse reactions in nursing infants from Ventavis, a decision to discontinue
`nursing should be made, taking into account the importance of the drug to the mother.
`
`Pediatric Use
`
`Safety and efficaCy in pediatric patients have not been established.
`
`Geriatric Use
`
`Clinical studies of Ventavis did not include sufficient numbers of subjects age 65 and older to
`determine whether they respond differently than younger subjects. Other reported clinical experience
`has not identified differences in responses between the elderly and younger patients. In general, dose
`selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
`reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant
`disease or other drug therapy.
`
`Hepatic or Renal Impairment
`
`Venlavis has not been studied in patients with pulmonary hypertension and hepatic or renal
`impairment, both of which increase mean AUC in otherwise normal subjects (see CLINICAL
`PHARMACOLOCY, Special Populations).
`
`ADVERSE REACTIONS
`
`Safety data on Ventavis were obtained From 215 patients with pulmonary arterial hypertension
`receiving iloprost in two 12-week clinical trials and two long-term extensions. Patients received
`inhaled Ventavis for periods of from 1 day to more than 3 years. The median number of weeks of
`exposure was 15 weeks. Forty patients completed 12 months of open-label treatment with iloprost.
`
`The following table shows adverse events reported by at least 4 iloprost patients and reported at least
`3% more frequently for iloprost patients than placebo patients in the 12-week placebo-controlled study.
`
`Adverse
`Event
`
`Placebo subtracted
`
`
`Table 2
`Adverse Events in Phase 3 Clinical Trial
`
`
`%
`Iloprost
`n= 10 l
`
`
`
`Vasodilation
`l 8
`
`
`
`
`(flushing)
`
`
`I Cough increased
`13
`
`
`Headache
`l 0
`
` 6
`
`
`
`
`
`5
`Nausea
`
`I Hypotension
`5.
`
`
`Vomitin ; 5
`
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`Alk -hos increased
`6
`
`
`Back .ain
`7
`3
`4
`
`Abnormal lab test
`_
`7
`3
`4
`
`Tongue pain
`_
`4
`0
`4
`
`Palpitations
`7
`4
`3
`Syncope
`8
`5
`3
`OCT increased
`6
`3
`3
`
`_
`
`
`
`
`
`
`WW
`Hemot sis
`Pneumonia
`
`6
`5
`4
`
`2
`l
`
`3
`3
`
`Serious adverse events reported with the use of inhaled iloprost and not shown in Table 2 include
`congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and
`kidney failure.
`
`Adverse events with higher doses
`
`In a study in healthy volunteers (n=16{)), inhaled doses of iloprost solution were given every 2 hours,
`beginning with 5 mcg and increasing up to 20 meg for a total of 6 dose inhalations (total cumulative
`dose of 70 mcg) or up to the highest dose tolerated in a subgroup of 40 volunteers. There were 13
`subjects (32%) who failed to reach the highest scheduled dose (20 meg). Five were unable to increase
`the dose because of (mild to moderate) transient chest painfdiscomfortftightness, usually accompanied
`by headache, nausea, and dizziness. The remaining 8 subjects discontinued for other reasons.
`
`OVERDOSAGE
`
`In clinical trials of Ventavis, no case of overdose was reported. Signs and symptoms to be anticipated
`are extensions of the dose-limiting pharmacological effects, including hypotension, headache, flushing,
`nausea, vomiting, and diarrhea. A specific antidote is not known. Interruption of the inhalation
`session, monitoring, and symptomatic measures are recommended.
`
`DOSAGE AND ADMINISTRATION
`
`Ventavis is intended to be inhaled using the Prodoseg AAD® System, a pulmonary drug delivery
`device. The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is well
`tolerated, dosing should be increased to 5 mcg and maintained at that dose. Ventavis should be taken 6
`to 9 times per day (no more than every 2 hours) during waking hours, according to individual need and
`tolerability. The maximum daily dose evaluated in clinical studies was 45 Inc g (5 mcg 9 times per
`day).
`
`Direct mixing of Ventavis with other medications in the Prodose AAD System has not been evaluated.
`To avoid potential interruptions in drug delivery due to equipment malfunctions, the patient should
`have easy access to a back-up Prodose AAD System.
`
`Each inhalation treatment requires one single-use ampule. Each single-use ampule delivers 20 meg/2
`mL to the medication chamber of the Prodose AAD System, and delivers a nominal dose of either 2.5
`mcg or 5.0 mcg to the mouthpiece.
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`For each inhalation session, the entire contents of one opened ampule of Ventavis should be transferred
`into the Prodose AAD System medication chamber immediately before use. After each inhalation
`session, any solution remaining in the medication chamber should be discarded. Use of the remaining
`solution will result in unpredictable dosing. Patients should follow the manufacturer’s instructions for
`cleaning the Prodose AAD System components after each dose administration.
`
`Preparation
`
`1. With one hand, hold the bottom of the ampule with the blue dot facing away from your body.
`El,
`x x.\
`\.
`
`2. With the other hand, wrap the included rubber pad around the entire ampule.
`ya
`I.
`
`3. Using your thumbs. break open the neck of the ampule by snapping the top towards you.
`
`4. Transfer the entire contents of the ampule into the medication chamber of the Prodose AAD
`System.
`
`5. Safely dispose of the open ampule out of the reach of children and as instructed by your
`healthcare practitioner.
`
`6. Follow the instructions provided by the drug manufacturer for administration of the Ventavis
`dose and maintenance of the Prodose AAD System .
`
`Use of Ventavis with other approved treatments for pulmonary hypertension has not been studied.
`Should patients deteriorate on this treatment, alternative treatments should be considered. Several
`patients whose status deteriorated while on Ventavis were successfully switched to intravenous
`epoprostenol.
`
`Dosage and Administration in Hepatic Impairment
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`Because iloprost elimination is reduced in patients with impaired liver fiinction (see CLINICAL
`PHARMACOLOGY and PRECAUTIONS), caution should be exercised during iloprost therapy in
`patients with at least Child Pugh Class B hepatic impairment.
`
`Dosage and Administration in Renal Impairment
`
`Dose adjustment is not required in patients not on dialysis. The effect of dialysis on iloprost is
`unknown. Use caution in treating patients on dialysis (see CLINICAL PHARMACOLOGY and
`PRECAUTIONS).
`
`HOW SUPPLIED
`
`Ventavis (iloprost) inhalation Solution is supplied in cartons of 30 or 100 clear glass single-use
`ampules (20 mcg iloprost per 2 mL ampule):
`
`30 ampule cartons: NDC 10148-101-30
`
`l00 ampule cartons: NDC 10148-101-01
`
`STORAGE
`
`Store at 20 — 25 °C (68 — 77 °F)
`
`Excursions permitted to 15 — 30 0C (59 — 86 0F)
`
`|See USP Controlled Room Temperaturel
`
`Distributed by:
`
`CoTherix, Inc.
`5000 Shoreline Court, Ste. 101
`South San Francisco, CA 94080
`
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`PATIENT INFORMATION
`
`Ventavis'" (ven TAY vis) Inhalation Solution
`(iloprost)
`
`Read the Patient Information that comes with Ventavis before you start using it and each time you get a refill.
`There may be new information. The leaflet does not take the place of talking with your doctor about your
`medical condition or your treatment.
`
`What is the most important information I should know about Ventavis?
`
`Ventavis may cause dizziness, Iightheadedness, and fainting (syncope) because
`it lowers your blood pressure. These are also common symptoms of PAH.
`
`To reduce your chances of fainting, stand up slowly when you get out of chairs or bed.
`Use Ventavis before increased physical exertion.
`Tell your doctor if fainting gets worse with Ventavis. Your doctor may need to adjust your dose or change
`your treatment.
`
`I
`
`Do not drive a car or operate any tools or machines if dizziness or fainting from lowr blood pressure is a
`problem for you.
`
`What is Ventavis"?
`
`Ventavis is a prescription medicine for adults with certain kinds of severe pulmonary arterial hypertension
`(PAH).
`[t is used to improve exercise ability and symptoms for a short time. PAH is a condition where blood
`pressure is too high in the blood vessels between the heart and the lungs.
`
`Ventavis has not been studied in children under the age of 18.
`
`How does Ventavis work?
`
`Ventavis lowers blood pressure within the pulmonary arteries by opening up the blood vessels in the lungs.
`
`What should I tell my doctor before starting Ventavis?
`
`Tell your doctor about all of your medical conditions including if you:
`
`I
`-
`
`-
`
`have liver or kidney problems. Your doctor may need to give you a lower dose of Ventavis.
`are pregnant, or planning to become pregnant. It is not known if Ventavis can harm your unborn baby.
`Ventavis should be used during pregnancy only if clearly needed. Women who can get pregnant should use
`effective birth control during treatment with Ventavis. Talk to your doctor about effective birth control
`methods.
`
`are breast-feeding. It is not known if Vcntavis passes into your milk. Talk to your doctor about the best
`way to feed your baby while using Ventavis.
`
`Tell your doctor about all the medicines you are taking including prescription and nonprescription
`medicines, vitamins, and herbal supplements. Ventavis and certain other medicines may affect each other in
`the way they work in your body. Be sure to tell your doctor if you take:
`- medicines used to treat high blood pressure or heart disease
`- medicines that decrease blood clotting
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`Keep a list of all the medicines you take. Show this list to your doctor and pharmacist each time you get a new
`medicine.
`
`How should I take Ventavis?
`
`See the end of this leaflet for instructions for using Ventavis with the Prodosc® AAD'K system.
`
`0 Take Ventavis exactly as prescribed by your doctor. Ventavis is usually used 6 to 9 times a day
`during waking hours. Your doctor will tell you how to space y0ur doses. You should take Ventavis
`when you wake up and also before any physical activity, but not more frequently than every 2 hours.
`Do not change your dose without talking to your doctor.
`0 Ventavis is breathed (inhaled) into your lungs with the help of a Prodose AAD device. One treatment
`session will usually last about 4 to 10 minutes.
`I Do not drink Ventavis.
`
`0
`
`0 Do not let Ventavis solution come into contact with your skin or eyes. If it does, rinse the skin or
`your eyes right away with water.
`If you take too much Ventavis, you may get a severe headache, chest pain, reddening of the face, j aw
`pain, dizziness, nausea, vomiting and diarrhea. If this happens stop taking Ventavis. if symptoms
`persist, call your doctor.
`I Do not allow other people to be exposed to Ventavis while you are breathing it, especially babies and
`pregnant women.
`
`What are the side effects with Ventavis?
`
`Ventavis may cause dizziness, lightheadness, and fainting (syncope) because it
`lowers your blood pressure. See "What is the most important information I
`should know about Ventavis?".
`
`The most common side effects with Ventavis include reddening ofthe face caused by dilation ofblood vessels
`(flushing), increased cough, low blood pressure (hypotension), headaches, nausea, spasm of the jaw muscles that
`causes trouble opening your mouth, and fainting (Syncopc).
`
`Talk to your doctor about any side effect that bothers you or that does not go away.
`
`These are not all of the side effects with Ventavis. For more information, ask your doctor or pharmacist.
`
`How should I store Ventavis?
`
`. Store Ventavis ampules at 68 to 77°F (20 to 25°C).
`.
`Safely dispose of Ventavis that is out of date or no longer needed.
`. Keep Ventavis and all medicines out of the reach of children.
`
`General Information about Ventavis
`
`Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not
`use Ventavis for a condition for which it was not prescribed. Do not give Ventavis to other people, even if they
`have the same Symptoms that you have.
`It may harm them.
`
`This leaflet summarizes the most important information about Ventavis. If you would like more information,
`talk with your doctor. You can ask your doctor or pharmacist for information about Ventavis that was written
`for healthcare professionals. Additional information can be found at www.cotherix.com or by calling 1-877-
`4VENTAVIS (1-877-483-6828).
`
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`What are the ingredients in Ventavis?
`
`Active ingredient: iloprost (as iloprost trometamol). Each 2-ml ampule contains 20 micrograms iloprost (as
`iloprost trometamol).
`Inactive ingredients: trometamol, ethanol, sodium chloride, hydrochloric acid 1'or pH adjustment, and water for
`injection.
`
`Instructions for using Ventavis with the Prodose AAD System
`
`Do not use Ventavis until your doctor or other healthcare provider has trained
`you on how to use the Prodose AAD system. Make sure you understand all the
`instructions or ask questions until you do.
`
`Ventavis should only be taken using the Prodose AAD System. The Prodose AAD system has been made to
`deliver the right dose of Ventavis. Using other devices is not recommended and other devices may not deliver
`the prescribed amount of Ventavis. Your doctor will give you the dosing disc for your Prodose AAD system.
`This dosing disc will control the amount of Ventavis you use. Do not change the dosing disc in your Prodose
`AAD System, without talking to your doctor.
`
`Do not put any other medicines in your Prodose AAD System while you are using Ventavis.
`
`To use Ventavis:
`
`1, Open the small glass bottle (ampule) of Ventavis by:
`a
`holding the ampule with the blue dot facing away from your body
`.i.
`
`‘\
`
`.
`
`- wrapping the included rubber pad around the ampule to protect from getting cut
`rd
`
`0
`
`using your thumbs to break open the neck of the ampule by snapping the top towards you
`
`2, Using the small tube (pipette) that comes with Ventavis, draw-up the entire amount of one ampule of
`Ventavis and empty it into the Prodose AAD System medicine chamber. The amount of Ventavis you
`
`receive will be controlled by the dosing disc that has been prescribed l‘or you.
`
`3. Safely dispose of the open ampule as taught by your doctor.
`
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`4, Follow the instructions that come with your Prodose AAD System 1'or using it to breathe in Ventavis. Each
`treatment session with Ventavis lasts about 4 to 10 minutes. The Prodose ADD System allows you to
`interrupt y0ur treatment I‘or up to ten minutes with no effect on the final dose you receive. If your treatment
`is interrupted for more than ten minutes, the Prodose AAD System will reset itself. In such cases, you
`should discard the remaining solution in the chamber and wait at least two hours before taking your
`next dose. Taking a second dose immediately could result in receiving too much medication.
`
`5, After each treatment dispose of any Ventavis that is left in the Prodose AAD System medicine chamber.
`Use of the remainder of Ventavis will not give you the right dose.
`
`6, Follow the instructions that come with the Prodose AAD System for cleaning it.
`
`7, Make sure you have a back-up Prodose AAD System to use for Ventavis treatments. This is especially
`important if your original Prodose AAD System does not work for some reason.
`
`UNITED THERAPEUTICS, EX. 2114
`WATSON LABORATORIES v. UNITED THERAPEUTI