NDA 21-??92’8-001 and 8-002
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`Page 3
`
`. ®
`VentaVIs
`
`(iloprost) Inhalation Solution
`
`Rx Only
`
`DESCRIPTION
`
`Ventavis (iloprost) Inhalation Solution is a clear, colorless, sterile solution containing 10 mcgr'rnL
`iloprost formulated for inhalation via either of two pulmonary drugr delivery devices: the I—neba'C AAD®
`(Adaptive Aerosol Delivery) System or the Prodose® AAD® System. Each single-use glass ampule
`contains 2 mL (20 mcg) of the solution to be added to the medication chamber of either pulmonary
`drug delivery device. Each mL of the aqueous solution contains 0.01 mg iloprost, 0.81 mg ethanol,
`
`0.121 mg trometharnine, 9.0 mg sodium chloride, and approximately 0.51 mg hydrochloric acid (for
`pH adjustment to 8.1) in water for inj ection. The solution contains no preservatives.
`
`The chemical name for iloprost is (ED-(3aS,4R,5R,6aS)-hexahydro-5-hydroxy—4-[(E)-(3S,4RS)-3-
`hydr0xy-4-methyl-l-octen-6-yny1]-A2(lm’A-pentalenevaleric acid.
`lloprost consists of a mixture of the
`4R and 4S diastereomers at a ratio of approximately 53:47.
`lloprost 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 C22H3204. Its relative molecular weight is 360.49. The structural
`formula is shown below:
`
`COOH
`
`CLINICAL PHARMACOLOGY
`
`General
`
`lloprost is a synthetic analogue of prostacyclin PGlg. lloprost 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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`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 pharmacokinetics over the dose range of l to 3
`ng/kgfmin. 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 p g/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 approximately 60% protein-bound, mainly to albumin, and this ratio is
`concentration-independent in the range of 30 to 3000 pgme.
`
`Metabolism and Excretion
`
`lloprost is metabolized principally via
`Clearance in normal subjects was appr0ximately 20 mLIminI’kg.
`[5-0xidati0n of the carbOxyl side chain. The main metabolite is tetranor—iloprost, which is found in the
`
`urine in free and conjugated form.
`inactive.
`
`In animal experiments, tetranor-iloprost was pharmacologically
`
`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 appr0ximately 10 er’mini’kg (half that of healthy subjects). Following oral
`administration, the mean AUCMh in Child Pugh Class B subjects (n= 3) was 1725 pg*hme compared
`
`to 117r pg* hme in normal subjects (n=4) receiving the same oral iloprost dose. In Child Pugh Class A
`
`subjects (n= 5), the mean AUCMh was 639 pg*hr'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 (n27), the mean AUCMh was 230 pg*MmL compared to 54 pg’l‘hme in patients
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`NDA 21-729fS-001 and 8-002
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`with renal failure (n=8) not requiring intermittent dialysis and 48 p g*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 sclerodenna, 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 PGIZ (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 mcgr’day)- The mean number of inhalations per day was 2.3. 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 UI’L, or total bilirubin
`3 5 mgr'dL), 4) rapidly progressive cardiogenic renal failure (e.g. decrease of estimated creatinine
`clearance to g 50% of baseline), 5) decrease in 6-minute walking distance by Z 30% of baseline value,
`6) new long-term need for i.v. catecholamines or diuretics, 7’) cardiac index 5 1.3 LI’minfmz, 8) CVP 3
`_ 22 mmHg despite adequate diuretic therapy, and 9) SVOZ _<_ 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 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-?79fS-001 and 8-002
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`Figure 1
`
`Composite Primary Endpoint for PAH Patients (WH0 Group I)
`
`- Ventavis (n=68)
`
`Placebo (n=78)
`
`2o
`1:
`1:
`
`after Inhalation
`
`oa
`
`.mo0
`
`:°
`3*
`
`B-Minute Walk
`10% Increase
`at 30 Minutes
`
`NYHA Class
`Improvement
`
`Death or
`Clinical
`Worsening
`
`Composite
`Clinical
`Endpoint
`
`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 21-7791’3-001 and 3-002
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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).
`
`I
`
`'l- h c:
`
`+ N O
`
`
`
`+0
`
`I
`
`N C)
`
`.L O
`
`I
`
`I
`
`+|Ioprost
`+Placebo
`
`o
`.E
`3W
`as
`.n
`:15>
`a:
`or
`
`c Eo
`
`33oI
`
`”
`.n
`ash
`
`ocNo E
`
`Basefine
`
`
`
`
`
`The effect of Ventavis in various subgroups is shown in Table 1.
`
`Table 1 Treatment Effects by Subgroup among PAH Patients (WHO Group I)
`
`
`Comp_osilc Clinical Endpoint
`6—Minu1c Walk gm)“
`Vcnlavis
`n
`Placebo
`Vcnlavis
`n
`n(%)
`—
`n§%1
`(meaniSD[
`—
`
`n
`—
`
`Placebo
`(meaniSD)
`
`n
`—
`
`All Subjects
`with PAH
`
`NYIIA III
`
`NYIIA IV
`
`Male
`
`Female
`
`Age 5 55
`
`Agc>55
`
`68
`
`13 (19%)
`
`78
`
`3 (4%)
`
`64
`
`31 i 76
`
`65
`
`—9 i T9
`
`40
`
`28
`
`23
`
`45
`
`41
`
`27
`
`7 (18%)
`
`6 (21%)
`
`5 (22%)
`
`8 (18%)
`
`6 (15%)
`
`?(26"o)
`
`47
`
`31
`
`24
`
`54
`
`40
`
`38
`
`2 (4%)
`
`1 (3%)
`
`0 (0%)
`
`3 (6%)
`
`2 (5%)
`
`l (3%)
`
`39
`
`25
`
`21
`
`43
`
`39
`
`25
`
`24 i T2
`
`43 i 82
`
`3? i 81
`
`29 i 74
`
`24 i 79
`
`42:1:71
`
`43
`
`22
`
`21
`
`44
`
`32
`
`33
`
`-16ct86
`
`6i63
`
`-22 j: 77
`
`-2 j: 81
`
`—5 i T8
`
`—13i8l
`
`* Change from baseline to 12 Weeks with measurement 30 minutes after dosing, based on all
`available data.
`
`Hemodynamic assessments obtained at week 12 before inhalation in both groups (at least 2 hours after
`a previous dose, trough) and after inhalation in the iloprost group (approximately 15 minutes after a
`
`dose, peak), are shown in Table 2. The relationship between hemodynamic changes and clinical
`effects is unknown.
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`NDA 21-?79l'S-001 and 8-002
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`Table 2 — Hemodynamic Parameters Before and After Iloprost Inhalation: Change from
`Baseline to Week 12
`
`
`Baseline
`Mean (i SD) change from baseline at Week 12
`
`Parameter
`[loprost
`Placebo
`Iloprost
`Placebo
`Before
`After Inhalation
`Inhalation
`
`
`PVR (dyn-s-cm '5)
`1029 i 390
`1041 i 493
`-9 i 275
`-239 i 279 (n=70)
`+96 1 323
`
`(n=?6)
`(11:77)
`
`mPAP(11‘In‘IHg)
`53 i 12
`54 i 14
`-[}.2 i T3
`-4.6 i 9.3
`-0.1 i 6.9
`
`(n=93)
`(n=90)
`(n=82)
`
`
`
`
`CO (Limin)
`
`3.8 i 1.1
`
`3.8 i 0.9
`
`+0.1 1 0.9
`
`(n=9l)
`
`SVO;(%)
`
`60:8
`
`60:8
`
`-l.l $7.6
`
`(n=72)
`
`+0.5 i 1.1
`
`(n=89)
`
`+1.8:8.3
`
`(n=70)
`
`-0.2 i 0.8
`
`(n=80)
`
`-3.2i6.7
`
`(n=63)
`
`In a small, randomized, double-blind, placebo-controlled study (the STEP trial), 34 patients treated
`with bosentan 125 mg bid for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6
`to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean
`number of inhalations per day was 5.6-
`
`INDICATIONS AND USAGE
`
`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).
`
`CONTRAINDICATIONS
`
`There are no known contraindications.
`
`WARNINGS
`
`Ventavis is intended for inhalation administration only via either of two pulmonary drug delivery
`devices: the I-neb‘i" AAD® System or the Prodose® AAD® System (See DOSAGE AND
`ADMINISTRATION). It has not been studied with any other nebulizers.
`
`In patients with low systemic blood
`Vital signs should be monitored while initiating Ventavis.
`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.
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`NDA 21-779fS-001 and 8-002
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`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 l-neb'E AAD'E System or the Prodosefi' AADE
`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 either of two
`pulmonary drug delivery devices, the I-nebj'i AAD'E System or the Prodosei"a AAD'E System, following
`the manufacturer’s instructions (see DOSAGE AND ADMINISTRATION). Patients should be
`trained in proper administration techniques including dosing fi'equency, ampule dispensing, I-nebfi
`AAD® System or Prodose® AAD® System operation, and equipment cleaning.
`
`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 dig0xin. 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 NMRUSPF mice. There was no evidence of a tumorigenic effect of
`
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`NDA 21-779/3-001 and 3-002
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`iloprost clathrate (13% iloprost by weight) in Sprague-Dawley rats dosed orally for up to 8 months at
`doses of up to 125 mgfkgr'day (Cmax of 45 ng/mL serum), followed by 16 months at 100 mg/kg/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 ngr'mL serum). The recommended clinical dosage regimen for iloprost (S
`mcg) affords a serum Cmax of 0. 16 ngi'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 mgi’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 ngt’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 l ngr'mL), no such digital anomalies or other gross-structural abnormalities were observed in
`the fetusest'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 l mgfkgfday. 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
`
`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
`
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`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 3
`Adverse Events in Phase 3 Clinical Trial
`
`Adverse
`Event
`
`Iloprost
`n=]0]
`
`Placebo
`n=102
`
`Placebo subtracted
`%
`
`__— ”‘
`
`flushin
`
`13
`
`10
`
`9
`
`m—— 6
`
`Nausea
`l3
`8
`5
`
`Hypotension
`l l
`6
`5
`
`Vomiting
`7
`2
`S
`
`Alk phos increased
`6
`1
`5
`Flu syndrome
`14
`10
`4
`Back uain
`7
`3
`4
`
`
`
`
`Tonue ain
`4
`0
`4
`
`Palpitations
`7
`4
`3
`
`Syncope
`8
`S
`3
`GGT increased
`6
`3
`3
`
`
`
`
`
`3 3
`
`3
`
`Muscle cram s
`
`6
`
`———_ 3
`
`Serious adverse events reported with the use of inhaled iloprost and not shown in Table 3 include
`congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and
`kidney failure.
`
`In a small clinical trial (the STEP trial, see CLINICAL TRIALS), safety trends in patients receiving
`concomitant bosentan and iloprost were consistent with those observed in the larger experience of the
`Phase 3 study in patients receiving only iloprost.
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`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 meg and increasing up to 20 mcg for a total of 6 dose inhalations (total cumulative
`dose of 7’0 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 painfdiscomfortftighmess, 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
`
`VentavislS intended to be inhaled using either of two pulmonary drug delivery devices: the I-neb®
`AAD® System or the Prodosefi’ AADR) System The first inhaled dose should be 2.5 mcg (as delivered
`at the mouthpiece). If this dose1s well tolerated, dosing should be increased to 5.0 mcg and maintained
`
`at that dose, otherwise maintain the dose at 2.5 mcg. Ventavis should be taken 6 to 9 times per day (no
`
`more than once every 2 hours) during waking hours, according to individual need and tolerability. The
`maximum daily dose evaluated in clinical studies was 45 mcg (5 me g 9 times per day).
`
`Direct mixing of Ventavis with other medications in the I-neb E MD” System or 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 I-neb?”AAD® System or 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 either the I-nebfi’ AAD'Z‘ System or F’rodosefl'b AADEE'L System, and
`delivers a nominal dose of either 2.5 mcg or 5.0 mcg to the mouthpiece.
`
`For each inhalation session, the entire contents of one opened ampule of Ventavis should be transferred
`into either the I—neb'g’ AAD® System or the Prodosefl'c' 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 I—nebE AAD® System or 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.
`
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`2. With the other hand, wrap the included rubber pad around the entire ampule.
`
`J .
`
`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 either the I-nebic
`AAD® System or the Prodose® AAD® System.
`
`5. Safely dispose of the open ampule and pipette as instructed by your healthcare practitioner.
`Keep both out of the reach of children.
`
`6. Follow the instructions provided by the drug manufacturer for administration of the Ventavis
`dose and maintenance of the I-nebK AADCR’ System or the Prodose'R AAD<K System.
`
`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
`
`Because iloprost elimination is reduced in patients with impaired liver fimction (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 meg iloprost per 2 mL ampule):
`
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`30 single-use ampule cartons: NDC 10148-101-30
`
`100 single-use ampule cartons: NDC 10148-101-01
`
`STORAGE
`
`Store at 20 — 25 ”C (68 — 77 0F)
`
`Excursions permitted to 15 — 30 °C (59 — 86 0F)
`
`[See USP Controlled Room Temperature]
`
`Distributed by:
`
`CoTherix, Inc.
`
`5000 Shoreline Court, Ste. 101
`
`South San Francisco, CA 94080
`
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`en aVIS
`V t
`'®(
`
`PATIENT INFORMATION
`0 u ID“
`ven
`VIS
`l1 a a IO"
`TAY ")Ihlt' Slt'
`(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 pulmonary
`arterial hypertension (PAH).
`
`To reduce your chances of fainting, stand up slowly when you get out of chairs or bed.
`0
`0 Use Ventavis before increased physical exertion.
`0
`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 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 Veutavis?
`
`Tell your doctor about all of your medical conditions including if you:
`
`0
`-
`
`0
`
`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
`
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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 Prodose‘fiJ AAD System or l-neb® AAD®
`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 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 the Prodose AAD System or l-ncb AAD
`System. One treatment session will usually last about 4 to 10 minutes.
`0 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.
`
`0
`
`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.
`0 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
`
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`for healthcare professionals. Additional information can be found at ww.4ventavis.com or by calling 1-877-
`4VENTAVIS (1-877-483-6828).
`
`What are the ingredients in Ventavis?
`
`Active ingredient: iloprost. Each 2-mL ampule contains 20 micrograms iloprost.
`Inactive ingredients: tromethamine, ethanol, sodium chloride, hydrochloric acid for pH adjustment, and water
`for injection.
`
`Instructions for using Ventavis with the Prodose AAD System or I-neb AAD System
`
`Do not use Ventavis until your doctor or other healthcare provider has trained
`you on how to use the Prodose AAD System or I—neb AAD system. Make sure you
`understand all the instructions or ask questions until you do.
`
`Ventavis should