NDA21-779
`Page 3
`
`Ventavis
`
`(iloprost) Inhalation Solution
`
`Rx Only
`
`DESCRIPTION
`
`Ventavis (iloprost) Inhalation Solutionis a clear, colorless, sterile solution containing 10 mcg/mL
`iloprost 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) ofthe solution
`to be added to the Prodose AAD System medication chamber. Each mLof the aqueoussolution
`contains 0.01 mg iloprost, 0.81 mg ethanol, 0.121 mg tromethamine, 9.0 mg sodium chloride, and
`approximately 0.51 mg hydrochloric acid (for pH adjustmentto 8.1) in water for injection. The
`solution contains no preservatives.
`
`The chemical nameforiloprost is (£)-(3aS,4R,5R,6aS)-hexahydro-5-hydroxy-4-|(£)-(3S,4RS)-3-
`hydroxy-4-methyl-1-octen-6-ynyl]-A7"””“-pentalenevaleric acid. Tloprost consists of a mixture of the
`4R and 4S diastereomersat 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 ofiloprost is C22H3204. Its relative molecular weight is 360.49. The structural
`formula is shown below:
`
`COOH
`
`CLINICAL PHARMACOLOGY
`
`General
`
`Iloprost is a synthetic analogue of prostacyclin PGh. Iloprost dilates systemic and pulmonary arterial
`vascular beds. It also affects platelet aggregation but the relevanceofthis effect to the treatment of
`pulmonary hypertension is unknown. The two diastereoisomersofiloprost differ in their potency in
`dilating blood vessels, with the 4S isomersubstantially more potent than the 4R isomer.
`
`Pharmacokinetics
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`General
`
`In pharmacokinetic studies in animals, there was no evidenceofinterconversion of the two
`diastereoisomersofiloprost. In human pharmacokinetic studies, the two diastereoisomers were not
`individually assayed.
`
`Iloprost administered intravenously has linear pharmacokinetics over the dose range of | to 3
`ng/kg/min. The half-life of iloprost is 20 to 30 minutes. Following inhalation of iloprost (5 mcg)
`patients with pulmonary hypertension haveiloprost peak serum levels of approximately 150 pg/mL.
`Tloprost was generally not detectable in the plasma 30 minutes to | hourafter inhalation.
`
`Absorption and Distribution
`
`The absolute bioavailability of inhaled iloprost has not been determined.
`
`Following intravenousinfusion, the apparent steady-state volumeofdistribution was 0.7 to 0.8 L/kg in
`healthy subjects. [loprost is approximately 60% protein-bound, mainly to albumin, and this ratio is
`concentration-independentin the range of 30 to 3000 pg/mL.
`
`Metabolism and Excretion
`
`Clearance in normal subjects was approximately 20 mL/min/kg. Iloprost is metabolized principally via
`8-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 pharmacologically
`inactive.
`
`Jn vitro studies reveal that cytochrome P450-dependent metabolism plays only a minorrole in the
`biotransformation ofiloprost.
`
`A mass-balancestudy using intravenously and orally administered [*H]-iloprostin healthy subjects
`(n=8) showedrecovery oftotal 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
`intravenousiloprost study in patients with liver cirrhosis, the mean clearance in Child Pugh Class B
`subjects (n = 5) was approximately 10 mL/min/kg (half that of healthy subjects). Following oral
`administration, the mean AUCo.gn in Child Pugh Class B subjects (n= 3) was 1725 pg*h/mL compared
`to 117 pg*h/mLin normal subjects (n=4) receiving the sameoral iloprost dose. In Child Pugh Class A
`subjects (n= 5), the mean AUC. was 639 pg*h/mL. Although exposure increased with hepatic
`impairment, there wasno effect onhalf-life.
`
`Renal Function Impairment
`
`Inhaled iloprost has not been evaluated in subjects with impaired renal function. However, in a study
`with intravenousinfusion ofiloprost in patients with end-stage renal failure requiring intermittent
`dialysis treatment (n=7), the mean AUCp.4, was 230 pg*h/mL comparedto 54 pg*h/mL in patients
`
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`NDA21-779
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`with renal failure (n=8) not requiring intermittent dialysis and 48 pg*h/mL in normals. Thehalf-life
`wassimilar 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 ClassIII or IV pulmonary arterial hypertension
`(PAH, WHO Group J; 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 PGI, (prostacyclin or its analogues) or endothelin
`receptor antagonists. Patients received 2.5 or 5.0 mcg ofiloprost by repeated inhalations 6 to 9 times
`per day during waking hours. The mean ageofthe entire study population was 52 years and 68% ofthe
`patients were female. The majority of patients (59%) were NYHAClassIII. 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 meg (range of 12.5 to 45 mcg/day). The mean numberofinhalations per day was 7.3. Ninety
`percentof patients in the iloprost group never inhaled study medication during the nighttime.
`
`The primary efficacy endpoint wasclinical response at 12 weeks, a composite endpoint defined by:a)
`improvementin exercise capacity (6-minute walk test) by at least 10% versus baseline evaluated 30
`minutes after dosing, b) improvementby at least one NYHAclass versus baseline, and c) no death or
`deterioration of pulmonary hypertension. Deterioration required two or more ofthe followingcriteria:
`1) refractory systolic blood pressure < 85 mmHg,2) worsening ofright heart failure with cardiac
`edema,ascites, or pleural effusion despite adequate backgroundtherapy, 3) rapidly progressive
`cardiogenic hepatic failure (e.g. leading to an increase of GOT or GPT to > 100 U/L,ortotal bilirubin
`> 5 mg/dL), 4) rapidly progressive cardiogenic renal failure (e.g. decrease of estimated creatinine
`clearance to < 50% ofbaseline), 5) decrease in 6-minute walking distance by > 30% ofbaseline value,
`6) new long-term need for i.v. catecholaminesor diuretics, 7) cardiac index < 1.3 L/min/m’, 8) CVP >
`_ 22 mmHgdespite adequate diuretic therapy, and 9) SVO» < 45%despite nasal O> 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 evidenceofbenefit in patients with
`pulmonary hypertension associated with chronic thromboembolic disease (WHO GroupIV); the
`results presented are therefore those related to patients with PAH (WHOGroupI). The responserate
`for the primary efficacy endpoint among PAHpatients was 19%for the iloprost group, compared with
`4% for the placebo group (p=0.0033). All three components of the composite endpoint favored iloprost
`(Figure 1).
`
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`NDA21-779
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`6-Minute Walk
`10%Increase
`at 30 Minutes
`after
`
`NYHA Class
`Improvement
`
`Inhalation
`
`[| Ventavis
`Placebo
`
`Death or
`Clinical
`Worsening
`
`Composite
`Clinical
`Endpoint
`
`The absolute change in 6-minute walk distance (Figure 2) measured (usingall available data and no
`imputation) 30 minutes after inhalation among patients with PAH wasgreaterin the iloprost group
`compared to the placebo groupatall 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
`comparedto placebo was approximately 60% of the effect seen at 30 minutesafter inhalation.
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`NDA21-779
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`Figure 2 — Change (Mean + SEM)in 6-Minute Walk Distance 30 Minutes post Inhalation in PAH
`Patients (WHO GroupI).
`
`—t— lloprost
`20-5 —m=—Placebo
`
`Baseline
`
`4 weeks
`
`8 weeks
`
`o £>wo
`
`O2 3>aaco<
`
`=oog s°W
`
`w27—°coo
`
`eE
`
`Theeffect of Ventavis in various subgroups is shown in Table 1.
`
`Table 1 Treatment Effects by Subgroup among PAH Patients (WHO Group I)
`
`12 weeks
`available data.
`
`Composite Clinical Endpoint
`6-Minute Walk*
`Placebo
`Ventavis
`n Placebo Ventavis n
`
`
`
`
`(mean + SD)
`(mean + SD)
`n
`
`
`
`
`with PAH
`
`All Subjects 13 (19%)|7868 3 (4%) 64 31+76 -9+79
`
`
`
`
`
`NYHA III
`
`NYHAIV
`
`Male
`
`Female
`
`40
`
`28
`
`23
`
`45
`
`7 (18%)
`
`6 (21%)
`
`2
`
`5 (22%)
`
`8 (18%)
`
`2 (4%)
`
`1 (3%)
`
`0 (0%)
`
`3 (6%)
`
`2 (5%)
`6 (15%)
`41
`Age < 55
`Age > 55 27=7 (26%)|: 1 (3%)
`
`
`
`
`
`* Change from baseline to 12 Weeks with measurement 30 minutes after dosing, based onall
`
`Treatment-related effects on hemodynamic measures (e.g. PVR, mPAP, CO, SVO3>) have not been
`demonstrated.
`
`INDICATIONS AND USAGE
`
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`NDA21-779
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`Ventavisis indicated for the treatment of pulmonary arterial hypertension (WHO GroupJ) in patients
`with NYHAClassIII or IV symptoms.In controlled trials, it improved a composite endpoint
`consisting of exercise tolerance, symptoms (NYHAClass), 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 Prodose® AAD®™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 occurin association with pulmonary arterial hypertension, particularly in association with
`physical exertion. The occurrenceofexertional syncope mayreflect 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 comeinto 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 hasnot 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 drugdelivery 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
`equipmentcleaning.
`
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`Patients should be advised that they may havea fall in blood pressure with Ventavis, so they may
`becomedizzy or even faint. They should stand up slowly whenthey 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 inhaledat 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 pharmacodynamicinteraction between intravenous
`iloprost and either nifedipine, diltiazem, 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 clinicaltrials, iloprost was used concurrently with anticoagulants, diuretics,
`cardiac glycosides, calcium channelblockers, analgesics, antipyretics, nonsteroidal anti-
`inflammatories, corticosteroids, and other medications. Intravenousinfusion of iloprost had no effect
`on the pharmacokinetics of digoxin. Acetylsalicylic acid did notalter the clearance (pharmacokinetics)
`of iloprost. Althoughclinical 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, Impairmentof Fertility
`
`Iloprost was not mutagenic in bacterial and mammaliancells in the presence or absence of extrinsic
`metabolic activation. Iloprost did not cause chromosomal aberrations in vitro in human lymphocytes
`and wasnot clastogenic in vivo in NMRI/SPF mice. There was no evidence of a tumorigenic effect of
`iloprost clathrate (13% iloprost by weight) in Sprague-Dawley rats dosedorally for up to 8 monthsat
`doses of up to 125 mg/kg/day (Cmax of 45 ng/mL serum), followed by 16 months at 100 mg/kg/day,
`or in Crl:CD-1®(ICR)BR albino mice dosedorally for up to 24 months at doses of up to 125
`mg/kg/day (Cmax of 156 ng/mL serum). The recommendedclinical dosage regimen foriloprost(5
`mcg) affords a serum Cmax of 0.16 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 Category C. In developmental toxicity studies in pregnant Han-Wistarrats, 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 (Cmaxof 90 ng/mL), in pregnantrabbits at intravenous dosagesof up to 0.5
`mg/kg/day (Cmax of 86 ng/mL), and in pregnant monkeysat 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 fetuses/pups. However, in gravid Sprague-Dawleyrats, iloprost clathrate (13% iloprost)
`significantly increased the number of non-viable fetuses at a maternally toxic oral dosage of 250
`mg/kg/day and in Han-Wistar rats was found to be embryolethal in 15 of44 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 onlyif the potential benefit justifies the potentialrisk to the
`fetus.
`
`Nursing Mothers
`
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`NDA 21-779
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`
`It is not known whether Ventavis is excreted in human milk. In studies with Han-Wistarrats, higher
`mortality was observed in pupsoflactating damsreceiving iloprost intravenously at 1 mg/kg daily. In
`Sprague-Dawleyrats, higher mortality was also observed in nursing pupsat a maternally toxic oral
`dose of 250 mg/kg/day ofiloprost clathrate (13% iloprost by weight). It is not known whetherthis
`drug is excreted in human milk. Because many drugs are excreted in human milk and becauseofthe
`potential for serious adverse reactions in nursing infants from Ventavis, a decision to discontinue
`nursing should be made, taking into account the importanceof the drug to the mother.
`
`Pediatric Use
`
`Safety and efficacy in pediatric patients have notbeen established.
`
`Geriatric Use
`
`Clinical studies of Ventavis did not include sufficient numbers of subjects age 65 and older to
`determine whetherthey respond differently than younger subjects. Other reported clinical experience
`has notidentified differences in responses betweenthe elderly and youngerpatients. In general, dose
`selection for an elderly patient should be cautious, usually starting at the low end ofthe 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
`
`Ventavis 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-weekclinicaltrials and two long-term extensions. Patients received
`inhaled Ventavis for periods of from | day to more than 3 years. The median numberof 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 reportedat least
`3%more frequently for iloprost patients than placebopatients in the 12-week placebo-controlled study.
`
`
`Table 2
`Adverse Events in Phase 3 Clinical Trial
`
`
`
`Adverse
`
`Event
`
`Placebo subtracted
`
`%
`
`
`
`Placebo
`lloprost
`n=101
`
`
`
`
`
`Vasodilation
`18
`
`
`(flushing)
`
`| Cough increased 13
`
`
`Headache
`10
`
`
`
`
`5
`Nausea
`
`
`| Hypotension
`5.
`
`
`Vomiting
`5
`
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`47 8
`
`NDA21-779
`Page 11
`
`
`
`
`
`Alk phos increased
`6
`
`Flu syndrome 14
`7
`Back pain
`Abnormallab test
`|
`7
`
`Tongue pain
`|
`Palpitations
`Syncope
`|
`GGTincreased
`Muscle cramps
`5
`Hemoptysis
`
`Pneumonia 4
`
`Lao|od|
`
`6
`6
`
`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
`kidneyfailure.
`
`Adverse events with higher doses
`
`In a study in healthy volunteers (n=160), inhaled doses of iloprost solution were given every 2 hours,
`beginning with 5 mcg and increasing up to 20 mcgfor 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 mcg). Five were unable to increase
`the dose because of (mild to moderate) transient chest pain/discomfort/tightness, 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 wasreported. Signs and symptomsto 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 Prodose® AAD®System, a pulmonary drug delivery
`device. Thefirst 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 maintainedat 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 evaluatedin clinical studies was 45 mcg (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 mcg/2
`mL to the medication chamberof the Prodose AAD System, and delivers a nominal doseof either 2.5
`meg or 5.0 mcg to the mouthpiece.
`
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`For eachinhalation 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 chambershould 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.
`
`Ao
`
`X
`
`S
`
`2. With the other hand, wrap the included rubber pad around the entire ampule.
`fr)
`1
`
`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 chamberof the Prodose AAD
`System.
`
`5. Safely dispose of the open ampule out of the reach of children andas 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 whosestatus deteriorated while on Ventavis were successfully switched to intravenous
`epoprostenol.
`
`Dosage and Administration in Hepatic Impairment
`
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`Becauseiloprost elimination is reduced in patients with impairedliver function (see CLINICAL
`PHARMACOLOGYand 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 adjustmentis not required in patients not on dialysis. The effect of dialysis on iloprostis
`unknown. Use caution in treating patients on dialysis (see CLINICAL PHARMACOLOGYand
`PRECAUTIONS).
`
`HOW SUPPLIED
`
`Ventavis (iloprost) Inhalation Solution is supplied in cartons of 30 or 100clear glass single-use
`ampules (20 mcg iloprost per 2 mL ampule):
`
`30 ampule cartons: NDC 10148-101-30
`
`100 ampule cartons: NDC 10148-101-01
`
`STORAGE
`
`Store at 20 — 25 °C (68 —77 °F)
`
`Excursions permitted to 15 — 30 °C (59 — 86 °F)
`
`[See USP Controlled Room Temperature]
`
`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)
`
`Readthe Patient Information that comes with Ventavis before you start using it and each time you getarefill.
`There may be new information. Theleaflet does not take the place of talking with your doctor about your
`medical condition or your treatment.
`
`Whatis the most important information I should know about Ventavis?
`
`Ventavis may cause dizziness, lightheadedness, and fainting (syncope) because
`it lowers your blood pressure. These are also common symptoms of PAH.
`
`To reduce your chancesof fainting, stand up slowly when you getout of chairs or bed.
`e
`e Use Ventavis before increased physical exertion.
`e
`Tell your doctorif fainting gets worse with Ventavis. Your doctor may need to adjust your dose or change
`your treatment.
`
`Do not drive a car or operate any tools or machinesif dizziness or fainting from low blood pressureis a
`problem for you.
`
`Whatis Ventavis ?
`
`Ventavis is a prescription medicine for adults with certain kinds of severe pulmonary arterial hypertension
`(PAH).
`It is used to improve exercise ability and symptomsfor a short time. PAH is a condition where blood
`pressure is too high in the blood vessels betweenthe heart and the lungs.
`
`Ventavis has not been studied in children underthe age of18.
`
`How does Ventavis work?
`
`Ventavis lowers blood pressure within the pulmonary arteries by opening up the blood vessels in the lungs.
`
`Whatshould I tell my doctor before starting Ventavis?
`
`Tell your doctor about all of your medical conditions includingif you:
`
`e
`¢
`
`¢
`
`haveliver 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 abouteffective birth control
`methods.
`are breast-feeding. It is not knownif Ventavis passes into your milk. Talk to your doctor aboutthe best
`way to feed your baby while using Ventavis.
`
`Tell your doctor aboutall the medicines you are taking including prescription and nonprescription
`medicines, vitamins, and herbal supplements. Ventavis and certain other medicines may affect each otherin
`the way they work in your body. Besure totell your doctor if you take:
`* medicines usedto treat high blood pressure or heart disease
`* medicines that decrease blood clotting
`
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`NDA 21-779
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`Keepa list of all the medicines you take. Show thislist to your doctor and pharmacist each time you get a new
`medicine.
`
`How should I take Ventavis?
`
`Seethe endofthis leaflet for instructions for using Ventavis with the Prodose” AAD"system.
`
`e 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 your doses. You should take Ventavis
`when you wake up andalso before any physical activity, but not more frequently than every 2 hours.
`Donot change your dose withouttalking to your doctor.
`e 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.
`e Do not drink Ventavis.
`¢ Do notlet Ventavis solution come into contact with your skin or eyes. If it does, rinse the skin or
`your eyes right away with water.
`Ifyou take too much Ventavis, you may get a severe headache, chest pain, reddening ofthe face, jaw
`pain, dizziness, nausea, vomiting and diarrhea. If this happens stop taking Ventavis. If symptoms
`persist, call your doctor.
`e Do not allow other people to be exposed to Ventavis while you are breathing it, especially babies and
`pregnant women.
`
`e
`
`Whatare the side effects with Ventavis?
`
`Ventavis may cause dizziness, lightheadness, and fainting (syncope) becauseit
`lowers your blood pressure. See "What is the most important information I
`should know about Ventavis?".
`
`The most commonside effects with Ventavis include reddening ofthe face caused by dilation of blood vessels
`(flushing), increased cough, low blood pressure (hypotension), headaches, nausea, spasm of the jaw musclesthat
`causes trouble opening your mouth, and fainting (syncope).
`
`Talk to your doctor about any side effect that bothers you or that does not go away.
`
`Theseare notall of the side effects with Ventavis. For more information, ask your doctor or pharmacist.
`
`How should I store Ventavis?
`
`e Store Ventavis ampules at 68 to 77°F (20 to 25°C).
`e
`Safely dispose of Ventavis that is out of date or no longer needed.
`e Keep Ventavis and all medicines out of the reach of children.
`
`General Information about Ventavis
`
`Medicines are sometimesprescribed for purposes otherthan thoselisted in Patient Informationleaflets. 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 symptomsthat 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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`NDA 21-779
`Page 16
`
`Whatarethe ingredients in Ventavis?
`
`Active ingredient: iloprost (as iloprost trometamol). Each 2-ml ampule contains 20 microgramsiloprost (as
`iloprost trometamol).
`Inactive ingredients: trometamol, ethanol, sodium chloride, hydrochloric acid for 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 howto 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 recommendedand other devices may not deliver
`the prescribed amountof 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 changethe dosing disc in your Prodose
`AADSystem, 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:
`®
`holding the ampule with the blue dot facing away from your body
`A
`
`~
`
`\,
`
`® wrapping the included rubber pad around the ampule to protect from getting cut
`a)
`i
`
`4
`
`¢
`
`using your thumbsto 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 emptyit into the Prodose AAD System medicine chamber. The amountof Ventavis you
`receive will be controlled by the dosing disc that has been prescribed for 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 for 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 your treatment for 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 chamberand 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 remainderof Ventavis will not give youthe right dose.
`
`6. Follow the instructions that come with the Prodose AAD System for cleaningit.
`
`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 somereason.
`
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