NDA 21-779
`Page 3
`
`
`Ventavis
`
`(iloprost) Inhalation Solution
`
`RX Only
`
`DESCRIPTION
`
`Ventavis (iloprost) Inhalation Solution is 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) of the solution
`to be added to the Prodose AAD System medication chamber. Each mL of the aqueous solution
`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 adjustment to 8.1) in water for injection. The
`solution contains no preservatives.
`
`The chemical name for iloprost is (E)-(3aS,4R,5R,6aS)-hexahydro-5-hydroxy-4-[(E)-(3S,4RS)-3-
`hydroxy-4-methyl-1-octen-6-ynyl]-∆2(1H),∆-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 C22H32O4. Its relative molecular weight is 360.49. The structural
`formula is shown below:
`
`
`
`COOH
`
`CH3
`
`OH
`
`OH
`
`
`CLINICAL PHARMACOLOGY
`
`
`
`General
`
`Iloprost is a synthetic analogue of prostacyclin PGI2. Iloprost dilates systemic and pulmonary 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.
`
`Pharmacokinetics
`
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`NDA 21-779
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`
`General
`
`In pharmacokinetic 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.
`
`Iloprost administered intravenously has linear pharmacokinetics over the dose range of 1 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 have iloprost peak serum levels of approximately 150 pg/mL.
`Iloprost 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 L/kg in
`healthy subjects. Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is
`concentration-independent in 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
`ß-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.
`
`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 mL/min/kg (half that of healthy subjects). Following oral
`administration, the mean AUC0-8h in Child Pugh Class B subjects (n= 3) was 1725 pg*h/mL compared
`to 117 pg*h/mL in normal subjects (n=4) receiving the same oral iloprost dose. In Child Pugh Class A
`subjects (n= 5), the mean AUC0-8h was 639 pg*h/mL. 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 AUC0-4h was 230 pg*h/mL compared to 54 pg*h/mL in patients
`
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`NDA 21-779
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`with renal failure (n=8) not requiring intermittent dialysis and 48 pg*h/mL 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 PGI2 (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 III. 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 U/L, or total bilirubin
`> 5 mg/dL), 4) rapidly progressive cardiogenic renal failure (e.g. decrease of estimated creatinine
`clearance to < 50% of baseline), 5) decrease in 6-minute walking distance by > 30% of baseline value,
`6) new long-term need for i.v. catecholamines or diuretics, 7) cardiac index < 1.3 L/min/m2, 8) CVP >
`22 mmHg despite adequate diuretic therapy, and 9) SVO2 < 45% despite nasal O2 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 I). The response rate
`for the primary efficacy endpoint among PAH patients 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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`NDA 21-779
`Page 6
`
`
`
`Figure 1 Composite Primary Endpoint for PAH Patients (WHO Group I)
`Ventavis
`
`43%
`
`26%
`
`
`
`25%
`
`8%
`
`13%
`
`4%
`
`6-Minute Walk
`10% Increase
`at 30 Minutes
`after
`Inhalation
`
`NYHA Class
`Improvement
`
`Death or
`Clinical
`Worsening
`
`Placebo
`
`p=0.0033
`
`19%
`
`4%
`
`Composite
`Clinical
`Endpoint
`
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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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`NDA 21-779
`Page 7
`
`Figure 2 – Change (Mean ± SEM) in 6-Minute Walk Distance 30 Minutes post Inhalation in PAH
`Patients (WHO Group I).
`
`
`
`
`Iloprost
`Placebo
`
`Baseline
`
`4 weeks
`
`8 w eeks
`
`12 weeks
`
`+40
`
`+20
`
`+0
`
` -20
`
` -40
`
`mean of absolute change vs. baseline
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The effect of Ventavis in various subgroups is shown in Table 1.
`
`Table 1 Treatment Effects by Subgroup among PAH Patients (WHO Group I)
`
`Composite Clinical Endpoint
`Ventavis
`n
`Placebo
`13 (19%)
`78
`3 (4%)
`
`n
`68
`
`n
`64
`
`6-Minute Walk*
`Ventavis
`n
`(mean ± SD)
`31 ± 76
`65
`
`Placebo
`(mean ± SD)
`-9 ± 79
`
`
`
`
`
`
`All Subjects
`with PAH
`
`
`
`
`
`
`
`
`
`-16±86
`43
`24 ± 72
`39
`2 (4%)
`47
`7 (18%)
`40
`NYHA III
`6±63
`22
`43 ± 82
`25
`1 (3%)
`31
`6 (21%)
`28
`NYHA IV
`
`
`
`
`
`
`
`
`
`-22 ± 77
`21
`37 ± 81
`21
`0 (0%)
`24
`5 (22%)
`23
`Male
`-2 ± 81
`44
`29 ± 74
`43
`3 (6%)
`54
`8 (18%)
`45
`Female
`
`
`
`
`
`
`
`
`
`-5 ± 78
`32
`24 ± 79
`39
`2 (5%)
`40
`6 (15%)
`41
`Age ≤ 55
`-13 ± 81
`33
`42 ± 71
`25
`1 (3%)
`38
`7 (26%)
`27
`Age > 55
`* Change from baseline to 12 Weeks with measurement 30 minutes after dosing, based on all
`available data.
`
`Treatment-related effects on hemodynamic measures (e.g. PVR, mPAP, CO, SVO2) have not been
`demonstrated.
`
`INDICATIONS AND USAGE
`
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`

`NDA 21-779
`Page 8
`
`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 Prodose® AAD® System, a pulmonary
`drug delivery device (See DOSAGE AND ADMINISTRATION). It has not been studied with any
`other nebulizers.
`
`Because of the risk of syncope, vital signs should be monitored while initiating Ventavis. In patients
`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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`NDA 21-779
`Page 9
`
`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 pharmacodynamic interaction 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 clinical trials, iloprost was used concurrently with anticoagulants, diuretics,
`cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-
`inflammatories, corticosteroids, and other medications. Intravenous infusion of iloprost had no effect
`on the pharmacokinetics of digoxin. Acetylsalicylic acid did not alter the clearance (pharmacokinetics)
`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
`
`Iloprost was not mutagenic in bacterial and mammalian cells in the presence or absence of extrinsic
`metabolic activation. Iloprost did not cause chromosomal aberrations in vitro in human lymphocytes
`and was not 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 dosed orally for up to 8 months at
`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 dosed orally for up to 24 months at doses of up to 125
`mg/kg/day (Cmax of 156 ng/mL serum). The recommended clinical dosage regimen for iloprost (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-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 fetuses/pups. 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
`mg/kg/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 benefit justifies the potential risk to the
`fetus.
`
`Nursing Mothers
`
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`

`NDA 21-779
`Page 10
`
`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/kg/day 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
`
`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-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.
`
`Table 2
`Adverse
`Event
`Vasodilation
`(flushing)
`Cough increased
`Headache
`Trismus
`Insomnia
`Nausea
`Hypotension
`Vomiting
`
`Adverse Events in Phase 3 Clinical Trial
`Iloprost
`Placebo
`n=101
`n=102
`27
`9
`
`39
`30
`12
`8
`13
`11
`7
`
`26
`20
`3
`2
`8
`6
`2
`
`Placebo subtracted
`%
`18
`
`13
`10
`9
`6
`5
`5.
`5
`
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`6
`14
`7
`7
`4
`7
`8
`6
`6
`5
`4
`
`NDA 21-779
`Page 11
`
`Alk phos increased
`Flu syndrome
`Back pain
`Abnormal lab test
`Tongue pain
`Palpitations
`Syncope
`GGT increased
`Muscle cramps
`Hemoptysis
`Pneumonia
`
`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
`
`1
`10
`3
`3
`0
`4
`5
`3
`3
`2
`1
`
`5
`4
`4
`4
`4
`3
`3
`3
`3
`3
`3
`
`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 mcg 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 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 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 Prodose® 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 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 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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`NDA 21-779
`Page 12
`
`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.
`
`
`2. With the other hand, wrap the included rubber pad around the entire ampule.
`
`
`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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`

`NDA 21-779
`Page 13
`
`Because iloprost elimination is reduced in patients with impaired liver function (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
`
`100 ampule cartons: NDC 10148-101-01
`
`STORAGE
`
`Store at 20 – 25 oC (68 – 77 oF)
`
`Excursions permitted to 15 – 30 oC (59 – 86 oF)
`
`[See USP Controlled Room Temperature]
`
`
`
`Distributed by:
`
`CoTherix, Inc.
`5000 Shoreline Court, Ste. 101
`South San Francisco, CA 94080
`
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`NDA 21-779
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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, lightheadedness, 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.
`
`
`Do not drive a car or operate any tools or machines if dizziness or fainting from low 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). It 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:
`
` •
`
` 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 Ventavis 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
`
`
`
`Liquidia's Exhibit 1029
`Page 12
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`

`NDA 21-779
`Page 15
`
`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 Prodose® AAD® system.
`
`• 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 and also before any physical activity, but not more frequently than every 2 hours.
`Do not change your dose without talking to your doctor.
`• 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.
`• Do not drink Ventavis.
`• 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, jaw
`pain, dizziness, nausea, vomiting and diarrhea. If this happens stop taking Ventavis. If symptoms
`persist, call your doctor.
`• 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 of the face caused by dilation of blood vessels
`(flushing), increased cough, low blood pressure (hypotension), headaches, nausea, spasm of the jaw muscles that
`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.
`
`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).
`
`Liquidia's Exhibit 1029
`Page 13
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`

`

`NDA 21-779
`Page 16
`
`
`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 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 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:
`• holding the ampule with the blue dot facing away from your body
`
`
`• wrapping the included rubber pad around the ampule to protect from getting cut
`
`
`• 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 for you.
`
`
`3. Safely dispose of the open ampule as taught by your doctor.
`
`
`
`Liquidia's Exhibit 1029
`Page 14
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`

`NDA 21-779
`Page 17
`
`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 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