NDA 21-779/S-001 and S-002
`Page 3
`
`- ®
`Ventavis
`
`(iloprost) Inhalation Solution
`
`Rx Only
`
`DESCRIPTION
`
`Ventavis (iloprost) Inhalation Solution 1s a clear,colorless, sterile solution containing 10 mcg/mL
`iloprost formulated for inhalation via either of two pulmonary drug delivery devices: the I-neb” AAD®
`(Adaptive Aerosol Delivery) System or the Prodose® AAD® System. Each single-use glass ampule
`contains 2 mL (20 mcg) ofthe solution to be added to the medication chamberofeither pulmonary
`drug delivery device. Each mL of the aqueoussolution contains 0.01 mgiloprost, 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 namefor iloprost is (£)-(3aS,4R,5R,6aS)-hexahydro-5-hydroxy-4-[(£)-(35,4RS)-3-
`hydroxy-4-methyl-1-octen-6-ynyl]-A””4_»entalenevaleric acid. Iloprost consists of a mixture ofthe
`4R and 4S diastereomersat a ratio of approximately 53:47.
`Iloprost is an oily substance, whichis
`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 S.
`
`The molecular formula of iloprost is C227H3204. Its relative molecular weight is 360.49. The structural
`formula is shownbelow:
`
`COOH
`
`CLINICAL PHARMACOLOGY
`
`General
`
`Iloprost is a synthetic analogue of prostacyclin PGI». 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 isomer substantially more potent than the 4R isomer.
`
`Pharmacokinetics
`
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`NDA 21-779/S-001 and S-002
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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. Thehalf-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 minutesto | hour after 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. Iloprost is approximately 60% protein-bound, mainly to albumin, andthisratio 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
`B-oxidation of the carboxyl side chain. The main metabolite is tetranor-iloprost, which is found in the
`urine in free and conjugated form.
`In animal experiments, tetranor-iloprost was pharmacologically
`inactive.
`
`In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minorrole in the
`biotransformation ofiloprost.
`
`A mass-balance study using intravenously and orally administered [*H]-iloprost in 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 AUC».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 AUCo.g, 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 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/mLin patients
`
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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 NYHAClassIII or IV pulmonary arterial hypertension
`(PAH, WHO GroupI; 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 mcg (range of 12.5 to 45 mcg/day). The mean numberofinhalations per day was 7.3. Ninety
`percent of 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 versusbaseline, and c) no death or
`deterioration of pulmonary hypertension. Deterioration required two or more of the followingcriteria:
`1) refractory systolic blood pressure < 85 mmHg, 2) worseningofright 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,ortotal bilirubin
`> 5 mg/dL), 4) rapidly progressive cardiogenic renalfailure (e.g. decrease of estimated creatinine
`clearance to < 50% of baseline), 5) decrease in 6-minute walking distance by > 30% ofbaseline value,
`6) new long-term needforiv. catecholaminesordiuretics, 7) cardiac index < 1.3 L/min/m’, 8) CVP >
`_ 22 mmHgdespite 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 ofbenefit 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 GroupI). The response rate
`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/S-001 and S-002
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`Figure 1
`
`Composite Primary Endpoint for PAH Patients (WHO Group I)
`
`£o
`Ss
`
`'
`
`Ventavis (n=68)
`
`Placebo (n=78)
`
`p=0.0033
`
`19%
`
`c°2a®o
`
`xSo
`=
`
`6-Minute Walk
`10% Increase
`at 30 Minutes
`after Inhalation
`
`NYHAClass
`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 amongpatients with PAH wasgreaterin the iloprost group
`compared to the placebo groupat 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% ofthe effect seen at 30 minutes after inhalation.
`
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`NDA21-779/S-001 and S-002
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`Figure 2 — Change (Mean + SEM)in 6-Minute Walk Distance 30 Minutes post Inhalation in PAH
`Patients (WHO GroupI).
`
`® £ow
`
`o©a w
`
`o>
`
`12 weeks
`
`
`
`
`
`
`—hA— lloprost
`20 = —=— Placebo
`
`®Dco£a
`
`) £23w
`
`oa©—°co® E
`
`Baseline
`
`4 weeks
`
`8 weeks
`
`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
`6-Minute Walk (m)*
`Placebo
`h
`Ventavis
`n
`Placebo
`Ventavis
`n
`h
`(mean + SD)
`=
`n(%)
`~
`n(%)
`(mean + SD)
`=
`-
`
`
`All Subjects 13 (19%)|7868 3 (4%) 64 31+76 65 -9479
`
`
`
`
`
`with PAH
`
`NYHA III
`
`NYHA IV
`
`Male
`
`Female
`
`Age <55
`
`Age > 55
`
`40
`
`28
`
`23
`
`45
`
`4]
`
`27
`
`7 (18%)
`
`6 (21%)
`
`5 (22%)
`
`8 (18%)
`
`6 (15%)
`
`7 (26%)
`
`47
`
`31
`
`24
`
`54
`
`40
`
`38
`
`2 (4%)
`
`1 (3%)
`
`0 (0%)
`
`3 (6%)
`
`2 (5%)
`
`1 (3%)
`
`39
`
`25
`
`21
`
`43
`
`39
`
`25
`
`24472
`
`43482
`
`37281
`
`29274
`
`24479
`
`4927]
`
`43
`
`22
`
`21
`
`44
`
`32
`
`33
`
`-16+86
`
`6463
`
`-22+77
`
`-2+81
`
`-5478
`
`-13+8]1
`
`* Change from baseline to 12 Weeks with measurement 30 minutes after dosing, based onall
`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 changesandclinical
`effects is unknown.
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`Table 2 — Hemodynamic Parameters Before and After [loprost Inhalation: Change from
`Baseline to Week 12
`
`Baseline
`Mean(+ SD) changefrom baseline at Week 12
`
`
`
`Parameter
`Tloprost
`Placebo
`Hloprost
`Placebo
`Before
`After Inhalation
`Inhalation
`
`
`
`
`
`
`PVR (dynesecm ~)|10294390|1041 +493 -9 +275 -239 + 279 (n=70) +96 + 323
`
`
`
`(n=76)
`(n=77)
`
`mPAP (mmHg)
`53+ ]2
`54+ 14
`-0.2 47.3
`46493
`-0.1+6.9
`
`(n=93)
`(n=90)
`(n=82)
`
`CO (L/min)
`
`3.84 1.1
`
`3.8+0.9
`
`+0.1+0.9
`
`(n=91)
`
`SVO>(%)
`
`6048
`
`60+8
`
`-1L.1+7.6
`
`(n=72)
`
`+0.54 1.1
`
`(n=89)
`
`+1.8+4 8.3
`
`(n=70)
`
`-0.2+0.8
`
`(n=80)
`
`-3.2+6.7
`
`(n=63)
`
`In a small, randomized, double-blind, placebo-controlled study (the STEPtrial), 34 patients treated
`with bosentan 125 mg bid for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 meg 6
`to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean
`numberofinhalations per day was 5.6.
`
`INDICATIONS AND USAGE
`
`Ventavis is indicated for the treatment of pulmonary arterial hypertension (WHO Group J) in patients
`with NYHAClassIII or [V symptoms.In controlledtrials, it improved a composite endpoint
`consisting of exercise tolerance, symptoms (NYHAClass), and lack of deterioration (see CLINICAL
`PHARMACOLOGY,Clinical Trials).
`
`CONTRAINDICATIONS
`
`There are no knowncontraindications.
`
`WARNINGS
`
`Ventavis is intended for inhalation administration only via either of two pulmonary drug delivery
`devices: the I-neb" 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 bealert 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 mayreflect a therapeutic gap or insufficient efficacy, and the
`need to adjust dose or change therapy should be considered.
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`Should signs of pulmonary edemaoccur wheninhaled 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 I-neb” AAD” System or 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 advisedto use the drug only as prescribed with either of two
`pulmonary drug delivery devices, the I-neb" AAD” System or the Prodose” AAD” System, following
`the manufacturer’s instructions (see DOSAGE AND ADMINISTRATION). Patients should be
`trained in proper administration techniques including dosing frequency, ampule dispensing, I-neb*
`AAD*®System or Prodose® AAD® System operation, and equipmentcleaning.
`
`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 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 notlast 2 hours.
`
`DrugInteractions
`
`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 clinical trials, iloprost was used concurrently with anticoagulants, diuretics,
`cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-
`inflammatories, corticosteroids, and other medications.
`Intravenousinfusion 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, ImpairmentofFertility
`
`Iloprost was not mutagenic in bacterial and mammalian cells in the presence or absence of extrinsic
`metabolic activation. Iloprost did not cause chromosomalaberrationsin vitro in human lymphocytes
`and wasnotclastogenic in vivo in NMRI/SPF mice. There wasno evidenceof a tumorigenic effect of
`
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`iloprost clathrate (13% iloprost by weight) in Sprague-Dawleyrats 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)BRalbino mice dosed orally for up to 24 monthsat doses of up to 125
`mg/kg/day (Cmax of 156 ng/mL serum). The recommendedclinical 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-
`Wistarrats at intravenous doses up to 1 mg/kg/day.
`
`Pregnancy
`
`Pregnancy Category C. In developmentaltoxicity 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 (Cmax of 90 ng/mL), in pregnantrabbits at intravenous dosages ofup 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 numberof 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 pregnancyonlyif 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-Wistarrats, higher
`mortality was observedin pups of lactating dams receiving iloprost intravenously at 1 mg/kg daily. In
`Sprague-Dawleyrats, 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 whetherthis
`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 youngerpatients. 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-weekclinicaltrials 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 byat least 4 iloprost patients and reportedat 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
`Iloprost
`Placebo
`Placebo subtracted
`Event
`n=101
`n=102
`%
`
`Vasodilation
`flushing
`
`27
`
`18
`
`|eSw
`
`
`We}oo)Go}ooo|BPR]B)BR)on]oy]un{oa]
`HET So
` th
`
` Hit
`
`[Trismus|8
`ano
`
`
`Nausea
`
`Hypotension
`Vomiting
`Alk phos increased
`Flu syndrome
`Back pain
`
`Abnormallab test
`Tongue pain
`
`Palpitations
`
`Syncope
`GGTincreased
`Muscle cramps
`|Hemoptysis,|ST
`an
`No
`[Pneumonia|CT
`ao
`
`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 clinicaltrial (the STEP trial, see CLINICAL TRIALS),safety trends in patients receiving
`concomitant bosentan and iloprost were consistent with those observed in the larger experience ofthe
`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 dosesofiloprost solution were given every 2 hours,
`beginning with 5 mcg andincreasing 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%) whofailed to reach the highest scheduled dose (20 mcg). Five were unableto 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 beanticipated
`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 either of two pulmonary drug delivery devices: the I-neb*
`AAD™ System or the Prodose” AAD” System. Thefirst inhaled dose should be 2.5 mcg (as delivered
`at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5.0 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 onceevery 2 hours) during waking hours, accordingto individual need andtolerability. The
`maximum daily dose evaluatedin clinical studies was 45 mcg (5 mcg 9 timesper day).
`
`Direct mixing of Ventavis with other medicationsin the I-neb® AAD® 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 accessto a back-up I-neb ® AAD® System or Prodose™
`AAD®* System.
`
`Eachinhalation treatment requires one single-use ampule. Each single-use ampule delivers 20 mcg/2
`mL to the medication chamberofeither the I-neb" AAD® System or Prodose® AAD® 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" AAD” System or 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 remainingsolution will result in unpredictable dosing. Patients should follow
`the manufacturer’s instructions for cleaning the I-neb” 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.
`AL
`
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`2. With the other hand, wrap the included rubberpad aroundthe entire ampule.
`
`a)
`
`3. Using your thumbs, break open the neck of the ampule by snapping the top towards you.
`
`4. Transfer the entire contents ofthe ampule into the medication chamberofeither the I-neb*
`AAD*System or the Prodose” AAD® System.
`
`5. Safely dispose of the open ampule andpipette as instructed by your healthcare practitioner.
`Keep both out of the reach of children.
`
`6. Follow theinstructions provided by the drug manufacturer for administration of the Ventavis
`dose and maintenanceofthe I-neb® AAD®System or the Prodose® AAD” System.
`
`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
`
`Becauseiloprost elimination is reduced in patients with impaired liver 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. Usecautionin treating patients on dialysis (see CLINICAL PHARMACOLOGYand
`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):
`
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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 °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® (
`TAYvis) Inhalation
`Soluti
`ven
`VIS
`nhalation Solution
`entavis
`(iloprost)
`
`Read the Patient Information that comes with Ventavis before you start using it and each time yougeta refill.
`There may be new information. The leaflet does not take the place of talking with your doctor about your
`medical condition or yourtreatment.
`
`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 pulmonary
`arterial hypertension (PAH).
`
`To reduce your chancesoffainting, stand up slowly when youget out 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.
`
`Donot drive a car or operate any tools or machinesif dizziness or fainting from low blood pressureis 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 symptomsfor a short time. PAHis a condition where bloodpressureis too high in the blood vessels
`betweenthe heart and the lungs.
`
`Ventavis has not been studied in children underthe age of 18.
`
`How does Ventavis work?
`
`Ventavis lowers blood pressure within the pulmonary arteries by opening up the blood vessels in the lungs.
`
`WhatshouldItell my doctor before starting Ventavis?
`
`Tell your doctor aboutall of your medical conditions including if you:
`
`e
`e
`
`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 whocanget 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 aboutthe best
`wayto 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 other in
`the way they work in your body. Be sureto tell your doctor if you take:
`* medicines usedto treat high blood pressure or heart disease
`* medicines that decrease blood clotting
`
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`Keepa 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 endofthis leaflet for instructions for using Ventavis with the Prodose” AAD System or I-neb" 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 doctorwill tell you how to space your doses. You should take Ventavis
`when you wakeup andalso before any physical activity, but not more frequently than every 2 hours.
`Donot change your dose without talking to your doctor.
`e Ventavis is breathed (inhaled) into your lungs with the help of the Prodose AAD System or I-neb AAD
`System. Onetreatment session will usually last about 4 to 10 minutes.
`Donot 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 breathingit, especially babies and
`pregnant women.
`
`e
`
`Whatare the side effects with Ventavis?
`
`Ventavis may causedizziness, lightheadness, and fainting (syncope) becauseit
`lowers your blood pressure. See "Whatis the most important information I
`should know about Ventavis?".
`
`The most commonside 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 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 purposesother 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 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
`
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`for healthcare professionals. Additional information can be found at www.4ventavis.com or by calling 1-877-
`4VENTAVIS(1-877-483-6828).
`
`What arethe ingredients in Ventavis?
`
`Active ingredient: iloprost. Each 2-mL ampule contains 20 microgramsiloprost.
`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 howto 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 only be taken using the Prodose AAD System or I-neb AAD System. The Prodose AAD
`System or J-neb AAD System has been madeto deliver the right dose of Ventavis. Using other devicesis not
`recommended and other devices maynot deliver the prescribed amount of Ventavis.
`
`If you are using the Prodose AAD System, your doctor will give you 2 dosing discs for your Prodose