--------------------- DOSAGE FORMS AND STRENGTHS----------------------
`Extended-Release Tablets: 0.125 mg, 0.25 mg, 1 mg, 2.5 mg and 5 mg. (3)
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`(cid:120) Severe hepatic impairment (Child Pugh Class C). (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS -----------------------
`(cid:120) Do not abruptly discontinue dosing. (2.5, 5.1)
`(cid:120) In patients with diverticulosis, Orenitram tablets can become lodged in a
`diverticulum. (5.2)
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`Most common adverse reactions (incidence >10%) reported in clinical studies
`in patients treated with Orenitram compared with placebo are headache,
`diarrhea, nausea, vomiting, jaw pain, and flushing. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
` ------------------------------ DRUG INTERACTIONS-------------------------------
`(cid:120) When co-administered with strong CYP2C8 inhibitors the initial dose is
`0.125 mg BID with 0.125 mg BID dose increments not more frequently
`than every 3 to 4 days. (2.4, 7.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 10/2019
`
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Hepatic Impairment
`8.7 Patients with Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Clinical Trials in Pulmonary Arterial Hypertension
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`17 PATIENT COUNSELING INFORMATION
`
`*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
`ORENITRAM safely and effectively. See Full Prescribing Information
`for ORENITRAM.
`ORENITRAM® (treprostinil) extended-release tablets, for oral use
`Initial U.S. Approval: 2002
` --------------------------- RECENT MAJOR CHANGES ---------------------------
`Indications and Usage (1.1)
`10/2019
`
` --------------------------- INDICATIONS AND USAGE ----------------------------
`Orenitram is a prostacyclin mimetic indicated for the treatment of pulmonary
`arterial hypertension (PAH) (WHO Group 1):
`(cid:120) To delay disease progression and to improve exercise capacity. The studies
`that established effectiveness included predominately patients with WHO
`functional class II-III symptoms and etiologies of idiopathic or heritable
`PAH (66%) or PAH associated with connective tissue disease (26%). (1.1)
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
`(cid:120) Give with food. Swallow tablets whole; use only intact tablets. (2.1)
`(cid:120) Starting dose: 0.125 mg TID or 0.25 mg BID. (2.1)
`(cid:120) Titrate by 0.125 mg TID or by 0.25 mg or 0.5 mg BID, not more frequently
`than every 3 to 4 days as tolerated. (2.1)
`(cid:120) If transitioning from intravenous (IV) or subcutaneous (SC) Remodulin®,
`the Orenitram dose should be increased while simultaneously decreasing
`the IV/SC infusion rate. (2.2)
`(cid:120) Mild hepatic impairment (Child Pugh Class A): Initiate at 0.125 mg BID.
`Increment at 0.125 mg BID not more frequently than every 3 to 4 days.
`(2.3)
`(cid:120) Avoid use in patients with moderate hepatic impairment. (2.3)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
` INDICATIONS AND USAGE
`1.1 Pulmonary Arterial Hypertension
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Transitioning from Subcutaneous or Intravenous Routes of
`Administration of Treprostinil
`2.3 Dose Adjustment in Patients with Hepatic Impairment
`2.4 Dose Adjustment for Use with CYP2C8 Inhibitors
`2.5 Interruptions and Discontinuation
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Worsening PAH Symptoms upon Abrupt Withdrawal
`5.2 Use in Patients with Blind-end Pouches
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-Marketing Experience
`7 DRUG INTERACTIONS
`7.1 Effect of CYP2C8 Inhibitors on Treprostinil
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`
`
`
`Liquidia's Exhibit 1074
`Page 1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`1.1 Pulmonary Arterial Hypertension
`Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group
`1) to delay disease progression and to improve exercise capacity.
`
`The studies that established effectiveness included predominately patients with WHO functional
`class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with
`connective tissue disease (26%).
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`Take Orenitram with food. Swallow Orenitram tablets whole; do not crush, split, or chew.
`
`The recommended starting dose of Orenitram is 0.125 mg three times daily (TID) with food,
`taken approximately 8 hours apart or 0.25 mg twice daily (BID) with food, taken approximately
`12 hours apart.
`
`Titrate by 0.125 mg TID or 0.25 or 0.5 mg BID not more frequently than every 3 to 4 days.
`Increase the dose to the highest tolerated dose.
`
`If dose increments are not tolerated, consider titrating slower. If intolerable pharmacologic
`effects occur, decrease the dose in increments of 0.125 mg TID or 0.25 mg BID. Avoid abrupt
`discontinuation [see Warnings and Precautions (5.1)].
`
`2.2 Transitioning from Subcutaneous or Intravenous Routes of Administration of
`Treprostinil
`Decrease the dose of Remodulin while simultaneously increasing the dose of Orenitram. The
`dose of Remodulin can be reduced up to 30 ng/kg/min per day and the dose of Orenitram
`simultaneously increased up to 6 mg per day (2 mg TID) if tolerated. The following equation can
`be used to estimate a target total daily dose of Orenitram in mg using a patient’s dose of
`intravenous (IV)/subcutaneous (SC) treprostinil (in ng/kg/min) and weight (in kg).
`
`
`
`2.3 Dose Adjustment in Patients with Hepatic Impairment
`In patients with mild hepatic impairment (Child Pugh Class A) start at 0.125 mg BID with
`0.125 mg BID dose increments not more frequently than every 3 to 4 days. Avoid use of
`Orenitram in patients with moderate hepatic impairment (Child Pugh Class B). Orenitram is
`contraindicated in patients with severe hepatic impairment (Child Pugh Class C) due to increases
`in systemic exposure [see Contraindications (4), Use in Specific Populations (8.6), and Clinical
`Pharmacology (12.3)].
`
`2.4 Dose Adjustment for Use with CYP2C8 Inhibitors
`When co-administered with strong CYP2C8 inhibitors (e.g., gemfibrozil) the initial dose is
`0.125 mg BID with 0.125 mg BID dose increments not more frequently than every 3 to 4 days.
`
`
`
`Liquidia's Exhibit 1074
`Page 2
`
`

`

`
`
`2.5 Interruptions and Discontinuation
`If a dose of medication is missed, the patient should take the missed dose as soon as possible,
`with food. If a patient misses two or more doses, restart at a lower dose and re-titrate.
`
`In the event of a planned short-term treatment interruption for patients unable to take oral
`medications, consider a temporary infusion of subcutaneous or intravenous treprostinil. To
`calculate the total daily dose (mg) of treprostinil for the parenteral route use the following
`equation:
`
`
`When discontinuing Orenitram, reduce the dose in steps of 0.5 to 1 mg per day [see Warnings
`and Precautions (5.1)].
`
`3 DOSAGE FORMS AND STRENGTHS
`Orenitram (treprostinil) extended-release tablets are available in the following five strengths:
`- 0.125 mg [White tablet imprinted with UT 0.125]
`- 0.25 mg [Green tablet imprinted with UT 0.25]
`- 1 mg [Yellow tablet imprinted with UT 1]
`- 2.5 mg [Pink tablet imprinted with UT 2.5]
`- 5 mg [Red tablet imprinted with UT 5]
`
`4 CONTRAINDICATIONS
`Severe hepatic impairment (Child Pugh Class C) [see Use In Specific Populations (8.6) and
`Clinical Pharmacology (12.3)].
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Worsening PAH Symptoms upon Abrupt Withdrawal
`Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in
`worsening of PAH symptoms.
`
`5.2 Use in Patients with Blind-end Pouches
`The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a
`diverticulum.
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`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 clinical practice.
`
`In a 12-week, placebo-controlled, monotherapy study (Study 1; WHO Group 1; functional class
`II-III), and an event-driven, placebo-controlled, combination therapy study (Study 4;
`WHO Group 1; functional class I-III), the most commonly reported adverse reactions that
`occurred in patients receiving Orenitram included: headache, diarrhea, nausea, and flushing.
`
`
`
`Liquidia's Exhibit 1074
`Page 3
`
`

`

`
`
`Orenitram patients in Study 1 (N=151) had access to 0.25 mg tablets at randomization.
`Approximately 91% of such patients in Study 1 experienced an adverse reaction, but only 4%
`discontinued therapy for an adverse reaction (compared to 3% receiving placebo). Study 4
`enrolled a total of 690 patients, 346 received Orenitram and 344 received placebo. Overall, 19%
`of patients treated with Orenitram discontinued treatment in Study 4 due to an adverse event
`(compared to 4% of patients receiving placebo). The exposure to Orenitram in Study 4 was up to
`5.1 years with a median duration of exposure of 1.2 years. Table 1 summarizes adverse events
`with rates at least 5% higher on Orenitram therapy than on placebo that were reported in either
`Study 1 or 4.
`
`Table 1:
`
`Reaction
`
`Adverse Events with Rates at Least 5% Higher on Orenitram Therapy than
`on Placebo in Either Study 1 or Study 4
`Study 1
`N=228a
`Orenitram
`n=151
`63%
`30%
`30%
`17%
`15%
`11%
`14%
`
`Study 4
`N=690
`
`Orenitram
`n=346
`75%
`69%
`40%
`36%
`45%
`18%
`18%
`
`Placebo
`n=344
`35%
`29%
`23%
`10%
`8%
`3%
`9%
`
`Placebo
`n=77
`19%
`16%
`18%
`16%
`6%
`4%
`8%
`
`Headache
`Diarrhea
`Nausea
`Vomiting
`Flushing
`Pain in jaw
`Pain in
`extremity
`Hypokalemia
`Abdominal
`discomfort
`Upper
`abdominal pain
`a Includes all subjects in the Primary Analysis Population
`
`9%
`6%
`
`5%
`
`3%
`0%
`
`3%
`
`4%
`8%
`
`12%
`
`3%
`4%
`
`5%
`
`Orenitram was studied in a long-term, open-label, extension study in which 824 patients were
`dosed for a mean duration of approximately 2 years. About 70% of patients continued treatment
`with Orenitram for at least a year. The mean dose was 4.2 mg BID at one year. The adverse
`reactions were similar to those observed in the placebo-controlled trials.
`
`The safety of Orenitram was also evaluated in an open-label study transitioning patients from
`Remodulin. The safety profile during this study was similar to that observed in the three pivotal
`studies.
`
`6.2 Post-Marketing Experience
`The following adverse reactions have been identified during postapproval use of Orenitram:
`dizziness, dyspepsia, vomiting, myalgia, and arthralgia. Because these reactions are reported
`
`
`
`Liquidia's Exhibit 1074
`Page 4
`
`

`

`
`
`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.
`
`7 DRUG INTERACTIONS
`7.1 Effect of CYP2C8 Inhibitors on Treprostinil
`Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil in healthy adult
`volunteers increases exposure to treprostinil. Reduce the starting dose of Orenitram to 0.125 mg
`BID and use 0.125 mg BID increments not more frequently than every 3 to 4 days [see Dosage
`and Administration (2.4) and Clinical Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`Limited published data from case reports with Orenitram use in pregnant women are not
`sufficient to assess for a drug-associated risk of major birth defects, miscarriage, or adverse
`maternal or fetal outcomes. There are risks to the mother and the fetus associated with
`pulmonary arterial hypertension (see Clinical Considerations). Animal reproductive studies with
`treprostinil diolamine administered orally have shown an adverse effect on the fetus. In rats,
`administration of treprostinil to pregnant rats during the period of organogenesis at doses
`≥10 mg/kg/day (approximately 15 times the human exposure at the dose of 3.5 mg BID on an
`AUC basis) resulted in decreased pregnancy rate, increased post-implantation loss, and decreased
`fetal viability and growth. In rabbits, teratogenicity and decreased fetal viability and growth were
`observed at doses ≥1.5 mg/kg/day (approximately 7 times the human exposure at the dose of
`3.5 mg BID on an AUC basis) (see Animal Data).
`
`The estimated background risk of major birth defects and miscarriage for the indicated
`populations is unknown. All pregnancies have a background risk of birth defect, loss, or other
`adverse outcomes. In the U.S. general population, the estimated background risk of major birth
`defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
`respectively.
`
`Clinical Considerations
`Disease-associated maternal and embryo-fetal risk
`Pulmonary arterial hypertension in pregnancy increases the risk of maternal heart failure, stroke
`and death, preterm delivery, low birth weight, and stillbirth.
`
`Data
`Animal Data
`In pregnant rats, reversible, dose-dependent decreases in body weight gain and food consumption
`were observed during the first four days of dosing in animals administered 10, 20, and
`30 mg/kg/day treprostinil diolamine. In a dose range-finding study, there was a 17% decrease in
`the pregnancy rate in the animals administered 20 and 30 mg/kg/day. One dam in each of the
`20 and 30 mg/kg/day had litters with no viable fetuses. In the definitive study (0, 5, 10, and
`20 mg/kg/day), there were four treatment-related deaths, and a 32% decrease in the pregnancy
`rate for rats administered 20 mg/kg/day. There was an 8% decrease in the pregnancy rate in the
`animals administered 10 mg/kg/day. Across both studies, an increase in post-implantation loss
`was observed in animals administered 10 to 30 mg/kg/day, and a significant decrease in the mean
`number of live births was seen at dose levels ≥10 mg/kg/day. The no observed adverse effect
`level was 5 mg/kg/day (maternal, fetal viability and growth), and 20 mg/kg/day (teratogenicity),
`the highest dose tested in the definitive study. The exposures at 5 and 20 mg/kg/day doses
`
`
`
`Liquidia's Exhibit 1074
`Page 5
`
`

`

`
`
`represent 8 and 33 times, respectively, the human exposure at the dose of 3.5 mg BID on an AUC
`basis.
`
`For F1 progeny, a decreased copulation index was observed at the 5 and 10 mg/kg/day treprostinil
`diolamine dose levels in rats. The no observed effect levels for physical development, reflex
`development, exploratory behavior, learning and memory, and sexual maturation was
`10 mg/kg/day. The no observed effect level for F1 progeny general development (based on body
`weight) was 10 mg/kg/day for females and ≤2.5 mg/kg/day for males; the no observed effect level
`for F1 reproductive performance was 2.5 mg/kg/day (approximately 4 times the human exposure
`at the dose of 3.5 mg BID on an AUC basis).
`
`In pregnant rabbits, the primary maternal adverse effect was gastrointestinal disturbance;
`dose-dependent decreases in mean body weight, body weight gain, and food consumption were
`observed. During the post-dose phase, the effect was reversed. In a dose range-finding study,
`there was a 17% decrease in the pregnancy rate for animals administered 4 mg/kg/day. A
`dose-dependent increase in post-implantation loss was observed. Two dams administered
`4 mg/kg/day had litters with no viable fetuses; the mean fetal weight was slightly decreased in
`animals administered 4 mg/kg/day. In the definitive study, mean fetal weights were significantly
`decreased in animals administered 0.5 to 3 mg/kg/day of treprostinil diolamine. At doses of
`1.5 and 3 mg/kg/day, external fetal and soft tissue malformations were observed in a few fetuses,
`and the total fetal skeletal malformations were significantly increased. The no observed adverse
`effect level was less than 0.5 mg/kg/day (maternal), 1.5 mg/kg/day (fetal viability and growth),
`and 0.5 mg/kg/day (teratogenicity). The 0.5 mg/kg/day dose represents about 3 times the human
`exposure at the dose of 3.5 mg BID on an AUC basis.
`
`8.2 Lactation
`Risk Summary
`There are no data on the presence of treprostinil in human milk, the effects on the breastfed
`infant, or the effects on milk production.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`8.5 Geriatric Use
`Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and
`relative adverse event rates compared to younger patients. In general, dose selection for an
`elderly patient should be cautious, reflecting the greater frequency of decreased hepatic or cardiac
`function, and of concomitant disease or other drug therapy.
`
`8.6 Patients with Hepatic Impairment
`There is a marked increase in the systemic exposure to treprostinil in hepatically impaired
`patients [see Dosage and Administration (2.3), Contraindications (4), and Clinical
`Pharmacology (12.3)].
`
`8.7 Patients with Renal Impairment
`No dose adjustments are required in patients with renal impairment. Orenitram is not removed by
`dialysis [see Clinical Pharmacology (12.3)].
`
`
`
`Liquidia's Exhibit 1074
`Page 6
`
`

`

`
`
`10 OVERDOSAGE
`Signs and symptoms of overdose with Orenitram during clinical trials reflect its dose-limiting
`pharmacologic effects and include severe headache, nausea, vomiting, diarrhea, and hypotension.
`Treat supportively.
`
`11 DESCRIPTION
`Orenitram is an extended-release osmotic tablet for oral administration. Orenitram is formulated
`as the diolamine salt of treprostinil, a tricyclic benzindene analogue of prostacyclin. The
`chemical name is Acetic acid, 2-[[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-
`hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]-, complexed with 2,2’-iminobis[ethanol] (1:1). The
`molecular formula is C23H34O5.C4H11NO2, the molecular weight is 495.65, and it has the
`following structural formula:
`
`O
`
`CO2H
`
`OH
`
`NH
`
`HO
`
`.
`
`CH3
`
`H
`
`H
`
`HO
`H
`
`H
`
`HO
`
`H
`
`
`Orenitram tablets are formulated in five strengths, which contain 0.125 mg of treprostinil
`(equivalent to 0.159 mg treprostinil diolamine), 0.25 mg of treprostinil (equivalent to 0.317 mg
`treprostinil diolamine), 1 mg of treprostinil (equivalent to 1.27 mg treprostinil diolamine), 2.5 mg
`of treprostinil (equivalent to 3.17 mg treprostinil diolamine), or 5 mg of treprostinil (equivalent to
`6.35 mg treprostinil diolamine). The formulations also contain xylitol, maltodextrin, sodium
`lauryl sulfate, magnesium stearate, cellulose acetate, triethyl citrate, polyvinyl alcohol, titanium
`dioxide, polyethylene glycol, and talc. In addition, tablets may contain colorants FD&C Blue #2,
`iron oxide yellow, and iron oxide red. The imprint ink contains shellac glaze, ethanol, isopropyl
`alcohol USP, iron oxide black, n-butyl alcohol, and propylene glycol.
`
`Orenitram is designed to release treprostinil at a near zero-order rate using an osmotic tablet
`technology. The tablet core is coated with a semi-permeable membrane and has a laser-drilled
`aperture through the membrane. Upon contact with water (e.g., after ingestion), the core tablet
`absorbs water through the semi-permeable membrane. The water dissolves the water-soluble
`treprostinil diolamine and the water-soluble osmotic excipients, which creates hydrostatic
`pressure within the membrane, eventually forcing the drug across the membrane at a controlled
`rate.
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and
`systemic arterial vascular beds, inhibition of platelet aggregation, and inhibition of smooth
`muscle cell proliferation.
`
`
`
`Liquidia's Exhibit 1074
`Page 7
`
`

`

`
`
`12.2 Pharmacodynamics
`In a clinical trial of 240 healthy adult volunteers, single doses of inhaled treprostinil 54 μg (the
`target clinical dose) and 84 μg (supratherapeutic inhalation dose) prolonged the corrected QTc
`interval by approximately 10 msec. The QTc effect dissipated rapidly as the concentration of
`treprostinil decreased. Orenitram has not been evaluated in a thorough QTc study.
`
`12.3 Pharmacokinetics
`In patients with PAH, pharmacokinetics of treprostinil is dose-proportional for systemic exposure
`(AUC0-t) over the dose range from 0.5 to 15 mg BID. Upon repeat administration with a BID
`regimen, the accumulation in the systemic exposures to treprostinil is minimal and results in a
`peak-to-trough ratio of approximately 7. However, a TID regimen will reduce the peak-to-trough
`fluctuations to approximately 2.5 for the same total daily dose.
`
`Absorption
`The absolute oral bioavailability of Orenitram is approximately 17%. Maximum treprostinil
`concentrations occur between approximately 4 and 6 hours following Orenitram administration.
`Time to reach steady-state concentrations for both BID and TID regimens is approximately 1 to
`2 days.
`
`The absorption of Orenitram is affected by food. The AUCinf of treprostinil was increased by
`49% and the Cmax was increased by an average of 13% when Orenitram was administered
`following a high-fat, high-calorie meal compared to fasting conditions in healthy volunteers. The
`relative bioavailability of treprostinil following oral administration of Orenitram 1 mg is not
`significantly altered by meal types ranging from 250 to 500 calories in healthy volunteers.
`
`When Orenitram 1 mg was administered with alcohol at 0.5 mg/kg or the equivalent of 3 servings
`(at the same time, or ± 1 hour relative to alcohol consumption), there was no significant change
`(10% to 20% increase) in the exposure to treprostinil compared to Orenitram administered alone.
`
`Distribution
`The treprostinil component of Orenitram is highly bound to human plasma proteins,
`approximately 96% over a treprostinil concentration range of 0.01 to 10 μg/mL.
`
`Metabolism and Excretion
`In a study conducted in healthy volunteers using [14C] treprostinil, treprostinil was extensively
`metabolized on the side chain of the molecule via oxidation, oxidative cleavage, dehydration, and
`glucuronic acid conjugation. Treprostinil is primarily metabolized by CYP2C8 and to a lesser
`extent by CYP2C9. No new major metabolites are found upon oral administration compared to
`parenteral administration of treprostinil. Only 1.13% and 0.19% is excreted as unchanged parent
`drug in the feces and urine, respectively. Based on in vitro studies, treprostinil does not inhibit or
`induce major CYP enzymes [see Drug Interactions (7.1)].
`
`Specific Populations
`Hepatic Impairment: In subjects with mild (n=8) hepatic impairment, administration of a single
`1 mg dose of Orenitram resulted in a mean Cmax and an AUC0-inf that were 1.6- and 2.1-fold
`values seen in healthy subjects, respectively. With moderate impairment (n=8), the
`corresponding ratios were 4.0- and 4.8-fold, and with severe impairment (n=6), they were
`4.8- and 7.6-fold [see Dosage and Administration (2.3), Contraindications (4), and Use in
`Specific Populations (8.6)].
`
`
`
`Liquidia's Exhibit 1074
`Page 8
`
`

`

`
`
`Renal Impairment: In patients with severe renal impairment requiring dialysis (n=8),
`administration of a single 1 mg dose of Orenitram pre- and post-dialysis resulted in an AUC0-inf
`that was not significantly altered compared to healthy subjects.
`
`Drug Interactions
`Results of drug interaction studies are shown in Figure 1. Only for the strong CYP2C8 inhibitor
`does the interaction affect dosing [see Dosage and Administration (2.4)].
`
`Figure 1:
`
`Impact of Co-Administered Drugs on the Systemic Exposure of Treprostinil
`1 mg Compared to Orenitram Administered Alone
`
`
`
`
`
`
`
`Liquidia's Exhibit 1074
`Page 9
`
`

`

`
`
`Warfarin: A drug interaction study was carried out with Remodulin co-administered with
`warfarin (25 mg/day) in healthy volunteers. There was no clinically significant effect of either
`medication on the pharmacokinetics of treprostinil. Additionally, treprostinil did not affect the
`pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S-warfarin
`and the international normalized ratio (INR) in healthy subjects given a single 25 mg dose of
`warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate
`of 10 ng/kg/min.
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Treprostinil diolamine did not demonstrate any carcinogenic effects in mouse or rat
`carcinogenicity studies. Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5,
`10, and 20 mg/kg/day in males and 0, 3, 7.5, and 15 mg/kg/day in females daily for 26 weeks did
`not significantly increase the incidence of tumors. Oral administration of treprostinil diolamine to
`Sprague Dawley rats at 0, 1, 3, and 10 mg/kg/day daily for 104 weeks did not significantly
`increase the incidence of tumors. The exposures obtained at the highest dose levels used in males
`and females are about 13- and 18-fold, respectively, the human exposure at the dose of 3.5 mg
`BID on an AUC basis.
`
`In vitro genotoxicity studies with high doses of treprostinil did not demonstrate any mutagenic or
`clastogenic effects. Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did
`not induce an increased incidence of micronucleated polychromatic erythrocytes.
`
`In rats, treatment with treprostinil diolamine had no effect on reproductive performance or sperm
`motility at doses up to 10 mg/kg/day. The exposures at this dose level are about 6- (male) to
`11- (female) fold the human exposure at the dose of 3.5 mg BID on an AUC basis.
`
`14 CLINICAL STUDIES
`14.1 Clinical Trials in Pulmonary Arterial Hypertension
`Four multicenter, randomized, double-blind studies were conducted and compared Orenitram to
`placebo in a total of 349 (Study 1), 350 (Study 2), 310 (Study 3), and 690 (Study 4) patients with
`PAH.
`
`Study 1 (effect seen with no background vasodilator)
`Study 1 was a 12-week, randomized (2:1 Orenitram to placebo), double-blind, placebo-controlled,
`international efficacy and safety study of Orenitram in patients with WHO Group 1 PAH not
`currently receiving PAH therapy. The primary efficacy endpoint was placebo-corrected change in
`six-minute walk distance (6MWD) from Baseline to Week 12. Study drug dose was titrated to a
`maximum of 12 mg BID based on clinical response and study drug tolerability. Study 1 enrolled
`349 patients (overall analysis population) who were not receiving any PAH medication. At the
`beginning of the study, subjects were dosed with only the 1 mg tablets with 0.5 and 0.25 mg tablets
`introduced at sequentially later dates during the study. The primary analysis population consisted
`of the 228 patients who had access to the 0.25 mg tablet at the time of randomization. Patients were
`administered Orenitram or placebo twice daily, with the doses titrated to effect over the course of
`the 12-week trial. Patients were in WHO functional class II (~33%) and class III (~66%) with
`either idiopathic or heritable PAH (~75%), collagen vascular disease associated PAH (~19%), or
`PAH associated with HIV (1%) or congenital heart defect (5%) or other conditions (~6%). The
`patients' mean baseline 6MWD was approximately 330 meters. In the primary analysis population,
`17% of patients discontinued Orenitram compared to 14% of patients on placebo.
`
`
`
`Liquidia's Exhibit 1074
`Page 10
`
`

`

`
`
`The primary efficacy endpoint of the trial was the change in 6MWD at 12 weeks for the primary
`analysis population. Analysis of Study 1 results demonstrated that those patients receiving
`Orenitram compared to patients receiving placebo improved their median change in 6MWD by
`approximately 23 meters (p=0.013) as compared to patients receiving placebo as demonstrated in
`(Figure 2). The within group median change from baseline was +25 meters for Orenitram and
`-5 meters for placebo at Week 12 (N=228). Mean dose (±SD) in the Orenitram group was 2.3 ±
`1.3, 3.2 ± 1.9, and 3.4 ± 1.9 mg BID at Weeks 4, 8, and 12, respectively, with a maximum dose of
`12 mg BID. The distribution of the 6MWD change from baseline at Week 12 was also plotted
`across the range of observed values (Figure 3).
`
`Figure 2:
`
`Estimate of Treatment Effect by Visit for the Primary Analysis Population
`(Study 1)
`
`
`
`
`
`
`
`Liquidia's Exhibit 1074
`Page 11
`
`

`

`
`
`Figure 3:
`
`Plot of the Distribution of Peak 6MWD Changes at Week 12 for the Primary
`Analysis Population (Study 1)
`
`
`
`The placebo-corrected median treatment effect on 6MWD was estimated within various
`subpopulations defined by age, gender, disease etiology, and baseline 6MWD (Figure 4).
`
`
`
`
`
`Liquidia's Exhibit 1074
`Page 12
`
`

`

`
`
`Figure 4:
`
`Placebo Corrected Median Treatment Effect (with 95% CI) on 6MWD
`Change from Baseline at Week 12 for Various Subgroups in the Primary
`Analysis Population (Study 1)
`
`
`
`
`
`Studies 2 and 3 (no effect on a background of ERA, PDE-5 inhibitor, or both)
`Studies 2 (N=350) and 3 (N=310) were 16-week, randomized, double-blind, placebo-controlled,
`international efficacy and safety studies of Orenitram in patients with WHO Group 1 PAH. The
`primary efficacy endpoint was placebo-corrected change in 6MWD from Baseline to Week 16.
`Patients were in WHO functional class II (~23%) and class III (~77%) with either idiopathic or
`heritable PAH (~66%), collagen vascular disease associated PAH (~29%), or PAH associated
`with HIV (1%) or congenital heart defect (4%). The patients' mean baseline 6MWD was
`approximately 340 meters. Approximately 40% were receiving both an ERA and a PDE-5
`inhibitor. The results did not demonstrate a benefit in exercise testing with median 6MWD at
`Week 16.
`
`Study 4 (effect seen with a single background PAH therapy)
`The effect of Orenitram on the progression of PAH was demonstrated in an international,
`multicenter, double-blind, event-driven study in patients with WHO Group 1 PAH randomized 1:1
`to Orenitram or placebo (Study 4). The primary efficacy endpoint was the time to first clinical
`worsening (morbidity or mortality) event. Study drug dose was titrated starting at 0.125 mg TID to
`a maximum of 12 mg TID based on clinical response and study drug tolerability. Study 4 enrolled
`a total of 690 patients (primary efficacy analysis population) who were currently receiving a single
`
`
`
`Liquidia's Exhibit 1074
`Page 13
`
`

`

`
`
`approved PAH therapy (PDE-5 inhibitor or soluble guanylate cyclase (sGC) [72%]; ERA [28%]).
`The median age was 43 years and most patients were white (52%) and female (79%). The majority
`of patients were lower risk in WHO functional class II (63%) with a mean (±SD) baseline 6MWD
`of 396 (±96) meters. Most patients had either idiopathic or heritable PAH (63%) or collagen
`vascular disease associated PAH (26%).
`
`Patients treated with Orenitram achieved a median dose of 3.6 mg TID at Week 24, which
`continued to increase until approximately Week 60 where the median dose of Orenitram was
`approximately 5 mg TID.
`
`Treatment with Orenitram resulted in a significant increase in the time to first clinical worsening
`event compared with patients who received placebo, which was associated with a reduction in the
`risk of an event (HR=0.75 [95% CI; 0.57, 0.99]; p=0.039; Figure 5). The beneficial effect of
`Orenitram was primarily attributable to a delay in disease progression—defined as a 15% decline
`in 6MWD plus an increase in either WHO Functional Class or worsening of signs or symptoms of
`right heart failure—(HR=0.39 [95% CI; 0.23, 0.66]; Figure 6), but there was no effect on the
`other components of clinical worsening (Table 2).
`
`Figure 5:
`
`Kaplan-Meier Plot of Time to Clinical Worsening Events for the Primary
`Analysis Population (Study 4)
`
`
`OrenitramOrenitram
`
`PlaceboPlacebo
`
`
`
`120120
`
`81
`91
`
`
`
`P