`___________________ CONTRAINDICATIONS____________________
`
`
`None (4)
`
`_______________ WARNINGS AND PRECAUTIONS _______________
`
`
`Hypotension leading to syncope has been observed. Ventavis
`
`
`should not be administered in patients with systolic blood pressure
`
`below 85 mmHg (5.1).
`Pulmonary venous hypertension: Discontinue if pulmonary edema
`is present (5.2).
`
` May cause bronchospasm: Patients with a history of hyperreactive
`airway disease may be more sensitive (5.3).
`
`____________________ADVERSE REACTIONS ____________________
`
`
`Most common (>3% placebo adjusted) adverse reactions are vasodilation
`
`(flushing), cough increased, headache, trismus, insomnia, nausea,
`
`hypotension, vomiting, alkaline phosphatase increased, flu syndrome, back
`
`
`pain, tongue pain, palpitations, syncope, GGT increased, muscle cramps,
`hemoptysis, and pneumonia (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1­
`866-228-3546 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`____________________DRUG INTERACTIONS ____________________
`
`
`
`Ventavis has the potential to increase the hypotensive effect of
`
`vasodilators and antihypertensive agents (7.2).
`There is a potential for increased risk of bleeding, particularly in
`patients maintained on anticoagulants (7.3).
`
`_______________
`USE IN SPECIFIC POPULATIONS _______________
`
`
`Hepatic impairment: In patients with Child-Pugh Class B or C
`
`
`hepatic impairment, consider increasing the dosing interval (e.g.,
`3-4 hours between doses depending on the patient's response at the
`end of the dose interval) (2.3, 8.6).
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`preparation instructions
`
`
`Revised: 11/2013
`
`
` 
` 
`7.3 Anticoagulants and Platelet Inhibitors
` 
` 
`8. USE IN SPECIFIC POPULATIONS
`  
` 
`8.1 Pregnancy
` 
` 
`8.3 Nursing Mothers
` 
` 
`8.4 Pediatric Use
` 
` 
`8.5 Geriatric Use
` 
` 
`8.6 Hepatic Impairment
` 
` 
`8.7 Renal Impairment
` 
` 
`10. OVERDOSAGE
` 
` 
`11. DESCRIPTION
` 
` 
`12. CLINICAL PHARMACOLOGY
` 
` 
`12.1 Mechanism of Action
` 
` 
`12.3 Pharmacokinetics
` 
` 
`13. NONCLINICAL TOXICOLOGY
` 
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
` 
`14. CLINICAL STUDIES
` 
` 
`16. HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`17. PATIENT COUNSELING INFORMATION
` 
` 
`17.1 Preparation Instructions
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use VENTAVIS
`safely and effectively. See full prescribing information for VENTAVIS.
`
`VENTAVIS® (iloprost) inhalation solution
`
`Initial U.S. Approval: 2004
`
`For oral inhalation only
`
`
`_________________
`__________________ INDICATIONS AND USAGE
`
`Ventavis® is a synthetic analog of prostacyclin indicated for the treatment of
`pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a
`
`composite endpoint consisting of exercise tolerance, symptoms (NYHA
`
`Class), and lack of deterioration. Studies establishing effectiveness included
`predominately patients with NYHA Functional Class III-IV symptoms and
`etiologies of idiopathic or heritable PAH (65%) or PAH associated with
`connective tissue diseases (23%). (1.1).
` _______________
`______________
`DOSAGE AND ADMINISTRATION
`
`Ventavis is intended to be inhaled using the I-neb® AAD® System. Patients
`should receive 6 to 9 doses (inhalations) per day (minimum of 2 hours
`between doses during waking hours) as follows:
`
`Starting dose: 2.5 mcg (2.1).
`
`
`Uptitrate to 5 mcg if 2.5 mcg is well tolerated (2.1).
`
`
`
` Maintenance dose: 5 mcg (2.1).
`Delivered dose from ampule of :
`
`
` 10 mcg/mL
` 20 mcg/mL
`
`2.5 or 5 mcg from one
`5 mcg from one
`
`ampule
`ampule
`
`
`The 20 mcg/mL concentration is for patients who repeatedly
`experience extended treatment times (2.1).
`
`Vital signs should be monitored while initiating Ventavis (2.2).
`
`
`_____________
`______________ DOSAGE FORMS AND STRENGTHS
`
`
`1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL (3).
`
`
` Nebulizer
`
` I-neb AAD
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`_________________
`_________________
`TABLE OF CONTENTS
` 
`HIGHLIGHTS OF PRESCRIBING INFORMATION
` 
` 
`1.
`INDICATIONS AND USAGE
` 
` 
`1.1 Pulmonary Arterial Hypertension
` 
` 
`2. DOSAGE AND ADMINISTRATION
` 
` 
`2.1 Recommended Dosing
` 
` 
`2.2 Monitoring
` 
` 
`2.3 Use in Patients with Pre-existing Hepatic Impairment
` 
` 
`2.4 Use in Patients with Pre-existing Renal Impairment
` 
` 
`3. DOSAGE FORMS AND STRENGTHS
` 
` 
`4. CONTRAINDICATIONS
` 
` 
`5. WARNINGS AND PRECAUTIONS
` 
` 
`5.1 Risk of Syncope
` 
` 
`5.2 Pulmonary Venous Hypertension
` 
` 
`5.3 Bronchospasm
` 
` 
`6. ADVERSE REACTIONS
` 
` 
`6.1 Clinical Studies Experience
` 
` 
`6.2 Postmarketing Experience
` 
` 
`7. DRUG INTERACTIONS
` 
` 
`7.1 Cytochrome P450
` 
` 
`7.2 Antihypertensives and Vasodilators
`
`
`
`
`
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`
`
`1.
`
`INDICATIONS AND USAGE
`
`Pulmonary Arterial Hypertension
`1.1
` Ventavis® is indicated for the treatment of pulmonary arterial hypertension (PAH)
`
`(WHO Group 1) to improve a composite endpoint consisting of exercise tolerance,
`symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness
`included predominately patients with NYHA Functional Class III-IV symptoms and
`etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue
`diseases (23%) [see Clinical Studies (14)].
`
`2.
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosing
`2.1
` Ventavis is intended to be inhaled using the I-neb® AAD® System. 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 5.0 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 mcg 9 times per day).
`
`Direct mixing of Ventavis with other medications in the I-neb® AAD® System has not
`been evaluated; do not mix with other medications. 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.
`
`Ventavis is supplied in 1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.
`
`
`Nebulizer
`I-neb AAD
`
`
`The 20 mcg/mL concentration is intended for patients who are maintained at the 5 mcg
`dose and who have repeatedly experienced extended treatment times which could result
`in incomplete dosing. Transitioning patients to the 20 mcg/mL concentration using the I­
`
`neb AAD System will decrease treatment times to help maintain patient compliance.
`
`For each inhalation session, the entire contents of each opened ampule of Ventavis should
`
` be transferred into the I-neb® AAD® System medication chamber immediately before
`use [see Patient Counseling Information (17.1)]. 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-neb® AAD® System components after each dose
`administration.
`
`Delivered dose from ampule of :
`10 mcg/mL
`20 mcg/mL
`2.5 or 5 mcg from one ampule
`5 mcg from one ampule
`
`
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`
`
`Monitoring
`2.2
`Vital signs should be monitored while initiating Ventavis. [see Warnings and
`Precautions (5.1)].
`
`Use in Patients with Pre-existing Hepatic Impairment
`2.3
` Because iloprost elimination is reduced in patients with impaired liver function [see
`
`Special Populations (8.6)], consider increasing the dosing interval (e.g., 3-4 hours
`between doses depending on the patient's response at the end of the dose interval) in
`patients with Child-Pugh Class B or C hepatic impairment.
`
`Use in Patients with Pre-existing Renal Impairment
`2.4
`Dose adjustment is not required in patients who are not on dialysis. The effect of dialysis
`on iloprost is unknown [see Special Populations (8.7)].
`
`
`DOSAGE FORMS AND STRENGTHS
`3.
`1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.
`
`CONTRAINDICATIONS
`
`4.
`None
`
`WARNINGS AND PRECAUTIONS
`5.
`Ventavis solution should not be allowed to come into contact with the skin or eyes; oral
`ingestion of Ventavis solution should be avoided.
`
`Risk of Syncope
`5.1
`Monitor vital signs while initiating Ventavis. Do not initiate Ventavis in patients with
`
` systolic blood pressure below 85 mmHg. 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.
`
`Pulmonary Venous Hypertension
`5.2
`Should signs of pulmonary edema occur when inhaled Ventavis is administered in
`patients with pulmonary hypertension, stop treatment immediately, as this may be a sign
`of pulmonary venous hypertension.
`
`Bronchospasm
`5.3
`Ventavis inhalation can induce bronchospasm. Bronchospasm may be more severe or
`frequent in patients with a history of hyperreactive airways. Ventavis has not been
`
`evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma,
`or with acute pulmonary infections.
`
`
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`
`6.
`
`ADVERSE REACTIONS
`
`Clinical Studies Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical trials of a drug cannot be directly compared to rates in the
`clinical trials of another drug and may not reflect the rates observed in practice.
`
`Pre-marketing 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. Forty patients completed 12
`months of open-label treatment with iloprost.
`
`The following table shows adverse events reported by at least 4 Ventavis patients and
`reported at least 3% more frequently for Ventavis patients than placebo patients in the 12­
`week placebo-controlled study.
`
`Table 1: Adverse Events in Phase 3 Clinical Trial
`Adverse Event
`Ventavis
`Placebo
`n = 101
`n = 102
`
`
`27
`9
`
`Placebo subtracted
`%
`
`18
`
`Vasodilation
`
`
`(flushing)
`Cough increased
`Headache
`Trismus
`Insomnia
`Nausea
`Hypotension
`Vomiting
`Alk phos increased
`Flu syndrome
`Back pain
`Tongue pain
`Palpitations
`Syncope
`GGT increased
`Muscle cramps
`Hemoptysis
`Pneumonia
`
`Pre-marketing serious adverse events reported with the use of inhaled Ventavis and not
`shown in Table 1 include congestive heart failure, chest pain, supraventricular
`tachycardia, dyspnea, peripheral edema, and kidney failure.
`
`In a small clinical trial (the STEP trial) [see Clinical Studies (14)], safety trends in
`
`patients receiving concomitant bosentan and Ventavis were consistent with those
`
`39
`30
`12
`8
`13
`11
`7
`6
`14
`7
`4
`7
`8
`6
`6
`5
`4
`
`26
`20
`3
`2
`8
`6
`2
`1
`10
`3
`0
`4
`5
`3
`3
`2
`1
`
`13
`10
`9
`6
`5
`5
`5
`5
`4
`4
`4
`3
`3
`3
`3
`3
`3
`
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`
`
`observed in the larger experience of the Phase 3 study in patients receiving only Ventavis
`or bosentan.
`
`Adverse events with higher doses
`
`In a study in healthy subjects (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 subjects. 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.
`
`Postmarketing Experience
`6.2
`The following adverse reactions have been identified during the postapproval use of
`Ventavis. Because these reactions are reported voluntarily from a population of uncertain
`
`size, it is not always possible to reliably estimate their frequency or establish a causal
`relationship to drug exposure.
`
`Cases of bronchospasm and wheezing have been reported, particularly in patients with a
`history of hyperreactive airways [see Warnings and Precautions (5.3)]. Bleeding events
`most commonly reported as epistaxis and hemoptysis were observed on Ventavis
`treatment [see Drug Interactions (7.3)]. Cases of thrombocytopenia, dizziness, diarrhea,
`
`mouth and tongue irritation, nasal congestion, dysgeusia, hypersensitivity, and rash have
`also been reported with the use of Ventavis.
`
`DRUG INTERACTIONS
`7.
`During clinical trials, iloprost was used concurrently with anticoagulants, diuretics,
`cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-
`inflammatory drugs, 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.
`
`Cytochrome P450
`7.1
`Although clinical studies have not been conducted with Ventavis (inhaled iloprost), in
`vitro studies of iloprost indicate that no relevant inhibition of cytochrome P450 drug
`
`metabolism would be expected.
`
`Antihypertensives and Vasodilators
`7.2
`In studies in normal subjects, there was no pharmacodynamic interaction between
`intravenous iloprost and either nifedipine, diltiazem, or captopril. However, Ventavis has
`the potential to increase the hypotensive effect of vasodilators and antihypertensive
`agents.
`
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`
`Anticoagulants and Platelet Inhibitors
`7.3
`Since Ventavis inhibits platelet function, there is a potential for increased risk of
`bleeding, particularly in patients maintained on anticoagulants or platelet inhibitors.
`
`8.
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`
` Pregnancy Category C:
`Ventavis has been shown to be teratogenic in rats as described below. 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.
`
`
`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.
`
`Nursing Mothers
`8.3
` 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). In rats a passage of low levels of iloprost or
`
` metabolites in to the milk was observed (less than 1% of iloprost dose given
`intravenously). No disturbance of post-natal development and reproductive performance
`
`was seen in animals exposed during lactation. 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
`8.4
`Safety and efficacy in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`Clinical studies of Ventavis did not include sufficient numbers of subjects aged 65 and
`older to determine whether they respond differently than younger subjects. Other reported
`clinical experience has not identified differences in responses between elderly and
`younger patients. In general, dose selection for an elderly patient should be cautious,
`
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`
`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 Impairment
`8.6
`Ventavis 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 Impairment
`8.7
`Ventavis 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 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.
`
`OVERDOSAGE
`10.
`
`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.
`
`
`
`DESCRIPTION
`11.
`Ventavis (iloprost) Inhalation Solution is a clear, colorless, sterile solution containing
`iloprost formulated for inhalation via the I-neb® AAD® (Adaptive Aerosol Delivery)
`System. Ventavis is supplied in 1 mL single-use glass ampules containing either 10
`mcg/mL or 20 mcg/mL.
`
`
`For the 10 mcg/mL solution, one mL of the 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.
`
`
`For the 20 mcg/mL solution, one mL of the solution contains 0.02 mg iloprost, 1.62 mg
`
`ethanol, 0.242 mg tromethamine, 9.0 mg sodium chloride, and approximately 0.76 mg
`hydrochloric acid (for pH adjustment to 8.4) in water for injection.
`
`The solution contains no preservatives.
`
`
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`
`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]-Δ2(1H),Δ-pentalenevaleric
`acid.
`Iloprost
`consists of a mixture of the 4R and 4S diastereoisomers 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:
`
`
`
`
`12.
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Iloprost is a synthetic analog 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 diastereo­
`
`isomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer
`substantially more potent than the 4R isomer.
`
`Pharmacokinetics
`12.3
`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 plasma levels
`of approximately 150 pg/mL. Iloprost was generally not detectable in 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.
`
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`
` Metabolism and Excretion: In vitro studies reveal that cytochrome P450-dependent
`
`
`metabolism plays only a minor role in the biotransformation of iloprost. Iloprost is
`metabolized principally via β-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.
`
`Clearance in normal subjects was approximately 20 mL/min/kg.
`
`A mass-balance study using intravenously and orally administered [3H]-iloprost in
`healthy subjects (n=8) showed recovery of 81% of total radioactivity over 14 hours post-
`dose, with 68% and 12% recoveries in urine and feces, respectively.
`
`13.
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`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.
`
`CLINICAL STUDIES
`14.
`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 1; idiopathic in 53%, associated
`with connective tissue disease, including CREST and scleroderma, in 17%, or associated
`with anorexigen use in 2%) or PAH related to chronic thromboembolic disease (WHO
`
`Group 4; 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 digoxin, but not PGI2 (prostacyclin or its analogs) 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.
`
`
`
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`Reference ID: 3412463
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`The primary efficacy endpoint was clinical response at 12 weeks, a composite endpoint
`defined by: a) improvement in exercise ability (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 4); the results presented are therefore those related to patients with PAH
`(WHO Group 1). 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).
`
`
`
`
`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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`Reference ID: 3412463
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`
`
`Figure 2: Change (Mean ± SEM) in 6-Minute Walk Distance 30 Minutes Post-
`inhalation in PAH Patients (WHO Group 1).
`
`
`
`
`
`
` Ventavis
`n
`
`
`(mean ±SD)
`
`
`64
`31 ± 76
`
`
`
` 6-Minute Walk (m)*
`
`
`
` Placebo
`n
`
`
`(mean ±SD)
`
`65
`-9 ± 79
`
`
`39
`
`25
`
`21
`
`
`43
`
`
`24 ± 72
`
`43 ± 82
`
`
`37 ± 81
`
`29 ± 74
`
`43
`22
`
`21
`44
`
`
` -16 ± 86
`
`
`6 ± 63
`
`
`-22 ± 77
`
`-2 ± 81
`
`
`The effect of Ventavis in various subgroups is shown in Table 2.
`
`Table 2: Treatment Effects by Subgroup among PAH
`Patients (WHO Group 1)
`
` Composite Clinical Endpoint
`
`
`
`
`
`n
` Ventavis
`
`
` n (%)
`68
`13 (19%)
`
`40
`28
`
`23
`45
`
`
`7 (18%)
`
`6 (21%)
`
`
`5 (22%)
`8 (18%)
`
`
`
`n
` Placebo
`
`
` n (%)
`
`78
`3
`
`(4%)
`
`47
`31
`
`24
`54
`
`
`
`2 (4%)
`
`
`1 (3%)
`
`
`0 (0%)
`
`
`
`3 (6%)
`
`All Subjects
`with PAH**
`
`
`NYHA III
`NYHA IV
`
`Male
`
`Female
`
`Age ≤ 55
`
`Age > 55
`
`
`
`
`Reference ID: 3412463
`
`
`6 (15%)
`7
`
`40
`38
`
`
`2 (5%)
`
`
`1 (3%)
`
`
`39
`
`25
`
`
`
`24 ± 79
`
`42 ± 71
`
`32
`33
`
`
`-5 ± 78
`
`-13 ± 81
`
`41
`27
`
`
`(26%)
`* Change from baseline to 12 Weeks with measurement 30 minutes after dosing, based on all
`available data.
`** Etiologies of PAH, WHO Group 1 included idiopathic in 62% (n=90), associated with
`
`
`connective tissue disease, including CREST and scleroderma, in 17%, (n=25), associated with
`anorexigen use in 6% (n=9), heritable PAH in 3% (n=5), other PPH in 3% (n=5), SLE in 1%
`(n=2), post-partum in 1% (n=2), and overlap/other in 5% (n=8).
`
`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 3. The relationship
`between hemodynamic changes and clinical effects is unknown.
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`1029 ± 390 1041 ± 493
`
`
`Table 3 Hemodynamic Parameters Before and After Iloprost Inhalation: Change
`from Baseline to Week 12*
`Mean (± SD) change from baseline at Week 12
`
`Baseline
`
`Iloprost
`Placebo
`Parameter
`Iloprost
`Placebo
`Before
`
`
`
`
`Inhalation After Inhalation
`+96 ± 323
`-9 ± 275
`-239 ± 279
`
`PVR (dyn•s•cm–5)
`(n=77)
`(n=76)
`(n=70)
`
`
`
`
`-0.1 ± 6.9
`-0.2 ± 7.3
`-4.6 ± 9.3
`
`mPAP (mmHg)
`(n=82)
`(n=93)
`(n=90)
`
`
`
`
`-0.2 ± 0.8
`+0.1 ± 0.9
`+0.5 ± 1.1
`
`CO (L/min)
`(n=80)
`(n=91)
`(n=89)
`
`
`
`
`-3.2 ± 6.7
`-1.1 ± 7.6
`+1.8 ± 8.3
`SVO2 (%)
`
`60±8
`60 ± 8
`
`
`(n=63)
`(n=70)
`(n=72)
`
`
`
`
`*Patients of all etiologies of PAH, including CTEPH.
`
`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.
`
`53 ± 12
`
`
`54 ± 14
`
`
`3.8 ± 1.1
`
`
` 3.8 ± 0.9
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16.
`Ventavis (iloprost) Inhalation Solution is supplied in cartons of 30 x 1 mL clear glass
`single-use ampules as follows:
`
`1 mL ampule containing iloprost 10 mcg per mL, carton of 30 (NDC 66215-302-30)
`
`1 mL ampule containing iloprost 20 mcg per mL, carton of 30 (NDC 66215-303-30)
`
` STORAGE
`
`Store at 20 – 25°C (68 – 77°F)
`
`Excursions permitted to 15 – 30°C (59 – 86°F)
`
`[See USP Controlled Room Temperature]
`
`
`
`PATIENT COUNSELING INFORMATION
`17.
`Patients receiving Ventavis should be advised to use the drug only as prescribed with the
`I-neb® AAD® System, following the manufacturer’s instructions. Patients should be
`trained in proper administration techniques including dosing frequency, ampule
`dispensing, I-neb® AAD® System operation, and equipment cleaning.
`
`
`
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`Reference ID: 3412463
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`Advise patients 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.
`
`Advise patients 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. Thus patients may want to adjust
`times of administration to cover planned activities.
`
`See FDA-approved patient labeling.
`
`Preparation Instructions
`17.1
`Ventavis ampules may be opened with a rubber pad or with an ampule breaker.
`
`
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`Reference ID: 3412463
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`When using a rubber pad:
`
`1. With one hand, hold the bottom of the
`ampule with