throbber
NDA 21-779
`
`Page 3
`
`Ventavis
`
`(iloprost) Inhalation Solution
`
`Rx Only
`
`DESCRIPTION
`
`Ventavis (iloprost) Inhalation Solution is a clear, colorless, sterile solution containing 10 mch’mL
`iloprost formulated for inhalation via the Prodoseafl AADE (Adaptive Aerosol Delivery) System, a
`pulmonary drug delivery device. Each single-use glass ampule contains 2 mL (20 mcg) of the solution
`to be added to the Prodose AAD System medication chamber, Each mL of the aqueous solution
`contains 0.0] mg iloprost, 0.81 mg ethanol, 0.121 mg tromethamine, 9.0 mg sodium chloride, and
`approximately 0.51 mg hydrochloric acid (for pH adjustment to 8.1) in water for injection. The
`solution contains no preservatives.
`
`The chemical name for iloprost is (h)-(3aS,4R,5R,6aS)—hexahydro—5-hydroxy-4-[(h)-(3.S‘,4RS)-3-
`hydroxy-4-methyl-1-octen-6-ynyl]—A2(”DA-pentalenevaleric acid.
`lioprost consists of a mixture of the
`4R and 4S diastereomers at a ratio of approximately 53:47. Iloprost is an oily substance, which is
`soluble in methanol, ethanol, ethyl acetate, acetone and pH 7 buffer, sparingly soluble in buffer pH 9,
`and very slightly soluble in distilled water, buffer pH 3, and buffer pH 5.
`
`The molecular formula ofiloprost is C22H3204.
`formula is shown below:
`
`Its relative molecular weight is 360.49. The structural
`
`COOH
`
`CH 3
`
`4/
`
`(SH
`
`(iJH
`
`CLINICAL PHARMACOLOGY
`
`General
`
`Iioprost is a synthetic analogue of prostacyclin P612. Iloprost dilates systemic and pulmonary arterial
`vaSCular beds.
`It also affects platelet aggregation but the relevance of this effect to the treatment of
`pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in
`dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer.
`
`Pharmacokinetics
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page ‘I of 15
`
`

`

`NDA 21-779
`
`Page 4
`
`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.
`
`Iioprost administered intravenously has Einear pharmacokinetics over the dose range of l to 3
`ng/kg/min, The half-life ofiloprost is 20 to 30 minutes. Following inhalation ofiloprost (5 meg)
`patients with pulmonary hypertension have iloprost peak serum leveis of approximately 150 pg/m L.
`Iloprost was generally not detectable in the plasma 30 minutes to 1 hour after inhalation
`
`Absorption and Distribution
`
`The absolute bioavailability of inhaled iloprost has not been determined,
`
`Following intravenous infusion, the apparent steady-state volume of distribution was 0.7" to 0.8 Lfkg in
`healthy subjects, Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is
`concentration-independent in the range of 30 to 3000 pg/mL,
`
`Metabolism and Excretion
`
`iloprost is metabolized principally via
`Clearance in normal subjects was approximately 20 mLfminr’kg.
`S—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—iioprost was pharmacologically
`inactive.
`
`In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the
`biotransformation of iloprost.
`
`A mass-balance study using intravenously and oraily administered [3H]-iloprost in healthy subjects
`/
`(n=8) showed recovery of total radioactivity over 14 hours post-dose, was 81%, with 68% and 12%
`recoveries in urine and feces, respectively.
`
`Special Populations
`
`Liver Function Impairment
`
`Inhaled iloprost has not been evaluated in subjects with impaired hepatic function. However, in an
`intravenous iloprost study in patients with liver cirrhosis, the mean clearance in Child Pugh Class B
`subjects (n = 5) was approximately 10 mUminfkg (halfthat of healthy subjects). Following oral
`administration, the mean AUCU.3h in Child Pugh Class B subjects (n= 3) was 1725 pg’ihme compared
`to 117 pg’l‘hme in normal subjects (11:4) receiving the same oral iloprost dose. In Child Pugh Class A
`subjects (n= 5), the mean AUC0.gh was 639 pgt‘hi’mL. Although exposure increased with hepatic
`impairment, there was no effect on half-fife.
`
`Renal Function Impairment
`
`Inhaled iloprost has not been evaluated in subjects with impaired renal function, However, in a study
`with intravenous infusion of iloprost in patients with end-stage renal failure requiring intermittent
`dialysis treatment (n=7), the mean AUCn-4h was 230 pg*hme compared to 54 pg’l‘hme in patients
`
`WATSON LABORATORIES V- UNITED THERAPEUTICS, IPR2017—01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 2 of 15
`
`

`

`NDA 21-779
`
`Page 5
`
`with renal failure (n=8) not requiring intermittent dialysis and 48 pg*hi’mL in normals. The half-life
`was similar in both groups. The effect of dialysis on iloprost exposure has not been evaluated.
`
`Clinical Trials
`
`A randomized, doubie-blind, multi-center, placebo-controlled triai was conducted in 203 adult patients
`(inhaled iloprost: n=101; placebo: n=102) with NYHA Class ill or IV pulmonary arterial hypertension
`(PAH, WHO Group I; idiopathic in 53%, associated with connective tissue disease, including CREST
`and scleroderma, in 17%, or associated with anorexi gen 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 channei
`blockers), diuretics, oxygen, and digitalis, but not PGI; (prostacyciin 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 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 iioprost group, the median daily inhaled dose was
`30 mcg (range of 12.5 to 45 meg/day). The mean number ofinhaiations per day was 2.3. Ninety
`percent of patients in the iloprost group never inhaied 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 WT, or total bilirubin
`3 5 mg/dL), 4) rapidiy progressive cardiogenic renal failure (e.g. decrease of estimated creatinine
`clearance to f; 50% of baseline), 5) decrease in 6-minute walking distance by 3 30% ofbaseline value,
`6) new long-term need for i_v. catecholarnines or diuretics, 1’) cardiac index 5 1,3 Liminfmz, 8) CVP Z
`, 22 mmHg despite adequate diuretic therapy, and 9) SVO; 345% despite nasal 02 therapy.
`
`Although effectiveness was seen in the full population (response rates for the primary composite
`endpoint of 17% and 5%; p=0,00?), 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 eff] cacy endpoint among PAH patients was 19% for the iloprost group, compared with
`4% for the placebo group (p=0.003 3). All three components of the composite endpoint favored iloprost
`(Figure 1).
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 3 of 15
`
`

`

`NDA 21-779
`
`Page 6
`
`Fi rare 1Com )osite Primarv End nint for PAH Patients (WHO Grou l)
`Ventavis
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`
`
`
`
`i
`
`3
`
`3
`
`j
`
`.
`
`5
`
`5
`
`i
`
`:
`
`B-Minute Walk
`10% Increase
`at 30 Minutes
`after
`Inhalation
`
`NYHA Class
`Improvement
`
`Death or
`Clinical
`Worsening
`
`i
`3 Composite
`:
`3
`Clinical
`I
`j
`Endpoint
`1 ______________I
`
`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 ail 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.
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 4 of 15
`
`

`

`NDA 21-779
`
`Page ”I
`
`Figure 2 — Change (Mean :I: SE M) in 6-Minute Walk Distance 30 Minutes post Inhalation in PAH
`Patients (WHO Group I).
`
`a:
`.E
`3a:
`N
`.fl
`in->
`a)
`a:
`I
`.=
`:H
`
`Ua
`
`:«
`
`+|Ioprost
`+P|acebo
`
`Basehne
`
`Eom
`
`.D
`{I}h
`
`0:aU E
`
`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*
`
`
`11
`V nt vi
`n
`P}
`b
`n
`Ventavis
`n
`Placebo
`e
`a
`S
`ace 0
`(mean 3: SD)
`—
`(mean 4.— SD)
`13 (19%)
`3 (4%)
`31 a: 7'6
`65
`-9 i 79
`
`78
`
`64
`
`68
`
`
`
`
`
`
`
`
`
`All Subjects
`with PAH
`
`NYHA 111
`
`NYHA IV
`
`Male
`
`Female
`
`Age E 55
`
`Age > 55
`
`40
`
`28
`
`23
`
`4:3
`
`4]
`
`27
`
`7 (18%)
`
`6 (21%)
`
`5 (22%)
`
`8 (18%)
`
`6 (15%)
`
`7 (26%)
`
`4?
`
`31
`
`24
`
`54
`
`40
`
`38
`
`2 (4%)
`
`1 (3%)
`
`0 (0%)
`
`3 (6%)
`
`2 (5%)
`
`1 (3%)
`
`39
`
`25
`
`21
`
`43
`
`39
`
`25
`
`24 :t 72
`
`43 a: 82
`
`37 i 8]
`
`2‘) i 74
`
`24 i 79
`
`42 :I: 71
`
`43
`
`22
`
`21
`
`44
`
`32
`
`33
`
`-16i86
`
`6:63
`
`-22 i 7'7
`
`-2 d: 81
`
`-5 i 78
`
`-]3 i 81
`
`* Change from baseline to 12 Weeks with measurement 30 minutes after dosing. based on all
`available data.
`
`Treatment-related effects on hemodynamie measures (eg. PVR, mPAP, CO, SVOz) have not been
`demonstrated
`
`INDICATIONS AND USAGE
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IPR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 50f15
`
`

`

`NDA 21-779
`
`Page 8
`
`Ventavis is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients
`with NYHA Class III or IV symptoms. In controlled trials, it improved a composite endpoint
`consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration (see CLINICAL
`PHARMACOLOGY, Clinical Trials). Ventavis has not been adequately studied with concomitant
`use of other approved therapies for pulmonary arterial hypertension,
`
`CONTRAINDICATIONS
`
`There are no known contraindications.
`
`WARNINGS
`
`Ventavis is intended for inhalation administration only via the Prodose® AAD® System, a pulmonary
`drug delivery device (See DOSAGE AND ADMINISTRATiON).
`It has not been studied with any
`other nebulizers.
`
`In patients
`Because of the risk of syncope, Vital signs should be monitored while initiating Ventavis.
`with low systemic blood pressure, care should be taken to avoid further hypotension. Ventavis should
`not be initiated in patients with systolic blood pressure iess 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 exertions! syncope may reflect a therapeutic gap or insufficient
`efficacy, and the need to adjust dose or change therapy should be considered,
`
`Should signs of pulmonary edema occur when inhaled iloprost is administered in patients with
`pulmonary hypertension, the treatment should be stopped immediately. This may be a sign of
`pulmonary venous hypertension.
`
`PRECAUTIONS
`
`General
`
`Ventavis solution should not be allowed to come into contact with the skin or eyes; oral ingestion of
`Ventavis solution should be avoided.
`
`Direct mixing of Ventavis with other medications in the Prodose AAD System has not been evaluated.
`
`Ventavis has not been evaluated in patients with chronic obstructive pulmonary disease (COPD),
`severe asthma, or with acute pulmonary infections.
`
`Information for Patients
`
`Patients receiving Ventavis should be advised to use the drug only as prescribed with the Prodose
`AAD System, a pulmonary drug delivery device, following the manufacturer’s instructions (see
`DOSAGE AND ADMINISTRATION). Patients should be trained in proper administration
`techniques including dosing frequency, ampuie dispensing, Prodose AAD System operation, and
`equipment cleaning.
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 6 of 15
`
`

`

`NDA 21-779
`
`Page 9
`
`Patients should be advised that they may have a fall in blood pressure with Ventavis, so they may
`become dizzy or even faint. They should stand up slowly when they get out of a chair or bed. If
`fainting gets worse, patients should consult their physicians about dose adjustment.
`
`Patients should be advised that Ventavis should be inhaled at intervals of not less than 2 hours and that
`
`the acute benefits of Ventavis may not last 2 hours.
`
`Drug Interactions
`
`In studies in normal volunteers, there was no pharmacodynamic interaction between intravenous
`iloprost and either nifedipine, diltiazem, or captopril. However, iloprost has the potential to increase
`the hypotensive effect of vasodilators and antihypertensive agents. Since iloprost inhibits platelet
`function, there is a potential for increased risk of bleeding, particulariy in patients maintained on
`anticoagulants During clinical trials, iloprost was used concurrentiy with anticoagulants, diuretics,
`cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-
`inflammatories, corticosteroids, and other medications. Intravenous infusion of iloprost had no effect
`on the pharmacokinetics of digoxin. Acetyisalicylic 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
`
`lioprost was not mutagenic in bacteriai and mammalian cells in the presence or absence of extrinsic
`metabolic activation.
`lloprost 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
`iloprost cl athrate (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-i®(ICR)BR albino mice dosed orally for up to 24 months at doses of up to 125
`mgfkg/day (Cmax of 156 ng/mL serum). The recommended clinical dosage regimen for iloprost (S
`mcg) affords a serum Cmax of 0. 1 6 ng/mL. Fertility of males or females was not impaired in Han-
`Wistar rats at intravenous doses up to 't mg/kgl'day.
`
`Pregnancy
`
`Pregnancy Category C. In developmentai toxicity studies in pregnant Han-Wi star rats, continuous
`intravenous administration of iloprost at a dosage of 0.01 nag/kg daiiy (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
`mgfkg/day (Cmax of 86 ngKmL), and in pregnant monkeys at dosages of up to 004 mg/kg/day (serum
`levels of 1 ngme), no such digital anomalies or other gross-structural abnormalities were observed in
`the fetusesfpups. 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
`mgfkg/day and in Han-Wistar rats was found to be embryolethal in 15 of 44 litters at an intravenous
`dosage of 1 mg/kg/day. There are no adequate and well—controlled studies in pregnant women.
`Ventavis should be used during pregnancy only if the potential benefit justifl es the potential risk to the
`fetus.
`
`Nursing Mothers
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 7 of 15
`
`

`

`NDA 21-779
`
`Page 10
`
`It is not known whether Ventavis is excreted in human milk. In studies with Han-Wistar rats, higher
`mortality was observed in pups of lactating dams receiving iioprost 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 mgz’kg/day of iloprost ciathrate (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 ofthe
`potential for serious adverse reactions in nursing infants from Ventavis, a decision to discontinue
`nursing should be made, taking into acc0unt the importance of the drug to the mother.
`
`Pediatric Use
`
`Safety and efficacy in pediatric patients have not been established.
`
`Geriatric Use
`
`Ciinica] studies of Ventavis did not include sufficient numbers of subjects age 65 and older to
`determine Whether they respond differently than younger subj ects, Other reported clinical experience
`has not identified differences in responses between the elderly and younger patients.
`In general. dose
`selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
`reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant
`disease or other drug therapy.
`
`Hepatic or Renal Impairment
`
`Ventavis has not been studied in patients with pulmonary hypertension and hepatic or renal
`impairment, both of which increase mean AUC in otherwise normal subjects (see CLINICAL
`PHARMACOLOCY, Special Populations).
`
`ADVERSE REACTIONS
`
`Safety data on Ventavis were obtained from 215 patients with pulmonary arterial hypertension
`receiving iloprost in two 12-week clinical trials and two tong-term extensions. Patients received
`inhaled Ventavis for periods of from I 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 iioprost patients and reported at least
`3% more frequently for iloprost patients than placebo patients in the 12—week placebo—controlled study.
`
`
`Table 2
`Adverse Events in Phase 3 Clinical Trial
`
`Adverse
`Iloprost
`Placebo
`Placebo subtracted
`
`Event
`n=101
`n=102
`9-6
`
`Vasodilation
`2?
`9
`18
`
`(flushing)
`
`Cough increased
`39
`26
`13
`
`Headache
`30
`20
`10
`
`Trismus
`12
`3
`9
`
`Insomnia
`8
`2
`6
`
`Nausea
`13
`8
`5
`
`
`
`
`
`
`
`Hypotension
`Vomiting
`
`1 I
`7'
`
`6
`2
`
`5,
`5
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017—01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 8 of 15
`
`

`

`NDA 21-779
`
`Page 1 1
`
`
`Alk phos increased
`6
`l
`5
`
`Fiu syndrome
`14
`IO
`4
`
`Back pain
`7
`3
`4
`
`Abnormal lab test
`7
`3
`4
`
`Tongue pain
`4
`0
`4
`
`Palpitations
`7
`4
`3
`
`Syncope
`8
`5
`3
`
`GGT increased
`6
`3
`3
`
`
`
`
`
`Muscle cramps
`Hemoptysis
`Pneumonia
`
`6
`5
`4
`
`3
`2
`I
`
`3
`3
`3
`
`Serious adverse events reported with the use of inhaied iloprost and not shown in Table 2 include
`congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and
`kidney failure.
`
`Adverse events with higher doses
`
`in a study in healthy volunteers (n= 160), inhaled doses of iioprost solution were given every 2 hours,
`beginning with 5 mcg and increasing up to 20 mcg for a total of 6 dose inhalations (total cumulative
`dose of 70 mcg) or up to the highest dose tolerated in a subgroup of 40 volunteers. There were 13
`subjects (3 2%) who failed to reach the highest scheduled dose (20 mcg). Five were unable to increase
`the dose because of (mild to moderate) transient chest painfdiscomfortx’tightness, usually accompanied
`by headache, nausea, and dizziness. The remaining 8 subjects discontinued for other reasons.
`
`OVERDOSAGE
`
`In clinical trials of Ventavis, no case of overdose was reported. Signs and symptoms to be anticipated
`are extensions of the dose-limiting pharmacologicai effects, inciuding hypotension, headache, flushing,
`nausea, vomiting, and diarrhea. A specific antidote is not known, Interruption ofthe inhalation
`session, monitoring, and Symptomatic measures are recommended.
`
`DOSAGE AND ADMINISTRATION
`
`Ventavis is intended to be inhaled using the Prodoselfi! AAD® System, a pulmonary drug delivery
`device. The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is welt
`tolerated, dosing should be increased to 5 mcg and maintained at that dose. Ventavis should be taken 6
`to 9 times per day (no more than every 2 hows) during waking hours, according to individual need and
`tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per
`day)
`
`Direct mixing of Ventavis with other medications in the Prodose AAD System has not been evaluated.
`To avoid potential interruptions in drug delivery due to equipment malfunctions, the patient should
`have easy access to a back-up Prodose AAD System.
`
`Each inhalation treatment requires one single-use ampule. Each single-use ampule delivers 20 meg/2
`mL to the medication chamber of the Prodose AAD System, and delivers a nominal close of either 2.5
`mcg or 5.0 mcg t0 the mouthpiece.
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 9 of 15
`
`

`

`NDA 21-779
`
`Page 12
`
`For each inhalation session, the entire contents of one opened ampule of Ventavis should be transferred
`into the Prodose AAD System medication chamber immediately before use. After each inhalation
`session, any solution remaining in the medication chamber shouid be discarded. Use of the remaining
`solution will result in unpredictable dosing. Patients should follow the manufacturer’s instructions for
`cleaning the Prodose AAD System components after each dose administration,
`
`Preparation
`
`1. With one hand, hold the bottom of the ampule with the blue dot facing away from your body.
`
`to
`
`w
`
`4. Transfer the entire contents of the ampule into the medication chamber of the Prodose AAD
`System.
`
`
`
`5. Safely dispose of the open ampule out of the reach of children and as instructed by your
`healthcare practitioner.
`
`
`
`6, Follow the instructions provided by the drug manufacturer for administration of the Ventavis
`dose and maintenance of the Prodose AAD System .
`
`Use of Ventavis with other approved treatments for pulmonary hypertension has not been studied.
`Should patients deteriorate on this treatment, alternative treatments should be considered. Several
`patients whose status deteriorated while on Ventavis were successfully switched to intravenous
`epoprostenol .
`
`Dosage and Administration in Hepatic Impairment
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 10 of 15
`
`

`

`NDA 21-779
`
`Page 13
`
`Because iloprost elimination is reduced in patients with impaired liver function (see CLINICAL
`PHARMACOLOGY and PRECAUTIONS), caution should be exercised during iloprost therapy in
`patients with at least Child Pugh Class B hepatic impairment.
`
`Dosage and Administration in Renal Impairment
`
`Dose adjustment is not required in patients not on dialysis. The effect of dialysis on iloprost is
`unknown. Use caution in treating patients on dialysis (see CLINICAL PHARMACOLOGY and
`PRECAUTIONS).
`
`HOW SUPPLIED
`
`Ventavis (iloprost) Inhalation Solution is suppiied in cartons of 30 or 100 clear glass single-use
`ampules (20 mcg iloprost per 2 mL ampule):
`
`30 ampule cartons: NDC 10148-101 -30
`
`100 ampule cartons: NDC 10148—10'l—O'i
`
`STORAGE
`
`Store at 20 — 25 0C (68 — 7’? 0F)
`
`Excursions permitted to 15 — 30 0C (59 — 86 0F)
`
`{See USP Controlled Room Temperature]
`
`Distributed by:
`
`CoTherix, Inc.
`5000 Shoreline Court, Ste. 101
`
`South San Francisco, CA 94080
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 11 of 15
`
`

`

`NDA 21-779
`
`Page 14
`
`PATIENT INFORMATION
`
`Ventavism (ven TAY vis) Inhalation Solution
`(iloprost)
`
`Read the Patient Information that comes with Ventavis before you start using it and each time you get a refill.
`There may be new information. The leaflet does not take the place of talking with your doctor about your
`medical condition or your treatment
`
`What is the most important information I should know about Ventavis?
`
`Ventavis may cause dizziness, iightheadedness, and fainting (syncope) because
`it lowers your blood pressure. These are also common symptoms of PAH.
`
`I
`
`I
`I
`
`To reduce your chances of fainting, stand up slowiy when you get out of chairs or bed.
`
`Use Ventavis before increased physical exertion.
`Tell your doctor if fainting gets worse with Ventavis. Your doctor may need to adjust your dose or change
`you r 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 Ventavism?
`
`Ventavis is a prescription medicine for aduits with certain kinds of severe pulmonary arterial hypertension
`(PAH), It is used to improve exercise ability and symptoms for a short time, PAH is a condition where blood
`pressure is too high in the blood vessels between the heart and the lungs.
`
`Ventavis has not been studied in children under the age of IX.
`
`How does Ventavis work?
`
`Ventavis lowers blood pressure within the pulmonary arteries by opening up the blood vessels in the lungs.
`
`What should I tell my doctor before starting Ventavis‘?
`
`Tell your doctor about all of your medical conditions including if you:
`
`I
`
`I
`
`I
`
`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 Vcntavis can harm your unborn baby.
`Ventavis should be used during pregnancy only ifelearly 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
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 12 of 15
`
`

`

`NDA 21-779
`
`Page 15
`
`Keep a list ofall the medicines you take. Show this list to your doctor and phamiacist 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 Prodosex' AAD‘F; 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 close without taiking to your doctor.
`0 Ventavis is breathed (inhaled) into year lungs with the help of a Prodose AAD device, One treatment
`session will usually last about 4 to 10 minutes.
`Do not drink Ventavis.
`
`0
`
`-
`
`0
`
`t
`
`Do not let Ventavis solution come into contact with your skin or eyes. If it does, rinse the skin or
`your eyes right away with water.
`If you take too much Ventavis, you may get a severe headache= chest pain. reddening of the face: jaw
`pain, dizziness, nausea, vomiting and diarrhea. If this happens stop taking Ventavis. If symptoms
`persist, call your doctor.
`
`Do not allow other people to be exposed to Ventavis while you are breathing it, especially babies and
`pregnant women.
`
`What are the side effects with Ventavis?
`
`Ventavis may cause dizziness, Iightheadness, 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 ofthe 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 ofthc 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 Inform ation about Ventavis
`
`Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not
`use Vcntavis for a condition for which it was not prescribed. Do not give Ventavis to other people. even ifthey
`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,
`taik with your doctor. You can ask your doctor or pharmacist for information about Ventavis that was written
`for healthcarc professionals. Additional information can be found at www.cotlieiixcom or by calling 1-877-
`4VENTAVIS (l-8'r'7-483-6828).
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 13 of 15
`
`

`

`NDA 21-779
`
`Page 16
`
`What are the ingredients in Ventavis?
`
`Active ingredient: iloprost (as iloprost tromctamol). Each 2-mi ampule contains 20 micrograms iloprost (as
`iloprost trometamol).
`Inactive ingredients: tromctamol, ethanol, sodium chloride, hydrochioric acid for pH adjustment, and water for
`injection.
`
`Instructions for using Ventavis with the Prodose AAD System
`
`no not use Ventavis until your doctor or other healthcare provider has trained
`you on how to use the Prodose AAD system. Make sure you understand all the
`instructions or ask questions until you do.
`
`Ventavis should only be taken using the Prodosc AAD System. The Prodose AAD system has been made to
`deliver the right dose of Ventavis. Using other devices is not recommended and other devices may not deliver
`the pre scribed amount of Ventavis. Your doctor will give you the dosing disc for your Prodose AAD system.
`This dosing disc will control the amount of Ventavis you use. Do not change the dosing disc in your Prodose
`AAD System, without talking to your doctor.
`
`Do not put any other medicines in your Prodose AAD System while you are using Ventavis.
`
`To use Ventavis:
`
`1. Open the small glass bottle (ampulc) of Vcntavis by:
`
`a
`
`holding the ampule with the blue dot facing away from your body
`
`
`
` 0
`
`using your thumbs to break open the neck ofthe ampule by snapping the top towards you
`
`
`
`2. Using the small tube (pipette) that comes with Ventavis, draw-up the entire amount of one ampule of
`
`Ventavis and empty it into the Prodosc AAD System medicine chamber, The amount of Ventavis you
`
`receive will be controlled by the dosing disc that has been prescribed for you,
`
`3. Safely dispose of the open ampulc as taught by your doctor.
`‘~
`-.
`\.
`X -
`.
`\\
`
`
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017—01622
`
`UNITED THERAPEUTICS, EX. 2046
`
`Page 14 of 15
`
`

`

`NDA 21-779
`
`Page 17
`
`4. Follow the instructions that come with your Prodose AAD System for using it to breathe in Ventavis. Each
`treatment session with Ventavis lasts about 4 Lo 10 minutes. The Prodose ADD System allows you to
`interrupt your treatment for up to ten minutes with no effect on the final dose you receive, If your treatment
`is interrupted for more than ten minutes. the Prodose AAD System will reset itself.
`In such cases, you
`should discard the remaining solution in the chamber and wait at least two hours before taking your
`next dose. Taking a second dose immediately could result in receiving too much medication.
`
`5. After each treatment dispose of any Ventavis that is left in the Prodose AAD System medicine chamber.
`Use of the remainder of Ventavis will not give you the right dose.
`
`6. Follow the instructions that come with the Prodose AAD Syst

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket