`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203496Orig1s000
`LABELING
`
`
`
`

`

`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ORENITRAMTM safely and effectively. See Full Prescribing
`Information for ORENITRAM.
`ORENITRAM (treprostinil) Extended Release Tablets for oral
`administration
`Initial U.S. Approval: 2002
`----------------------------INDICATIONS AND USAGE---------------------------
`Orenitram is a prostacyclin vasodilator indicated for:
`•
`Treatment of pulmonary arterial hypertension (PAH) (WHO
`Group 1) to improve exercise capacity. The study that
`established effectiveness included predominately patients with
`WHO functional class II-III symptoms and etiologies of idiopathic
`or heritable PAH (75%) or PAH associated with connective tissue
`disease (19%). (1.1)
`As the sole vasodilator, the effect on exercise is small. Orenitram has
`not been shown to add to other vasodilator therapy. (1.1)
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`• Give with food. Swallow tablets whole; use only intact tablets.
`(2.1)
`Starting dose: 0.25 mg BID. (2.1)
`Titrate by 0.25 mg or 0.5 mg BID or 0.125 mg TID, not more than
`every 3 to 4 days as tolerated. (2.1)
`• Maximum dose is determined by tolerability. (2.1)
`• Mild hepatic impairment (Child Pugh Class A): Initiate at 0.125 mg
`BID. Increment at 0.125 mg BID every 3 to 4 days. (2.1)
`Avoid use in patients with moderate hepatic impairment. (2.1)
`
`•
`•
`
`•
`
`•
`•
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Extended Release Tablets: 0.125 mg, 0.25 mg, 1 mg and 2.5 mg. (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`•
`Severe hepatic impairment (Child Pugh Class C). (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`•
`Do not abruptly discontinue dosing. (2.2, 5.1)
`•
`Increased risk of bleeding, particularly in patients receiving
`anticoagulants. (5.2)
`Do not take Orenitram with alcohol (5.3)
`In patients with diverticulosis Orenitram tablets can become
`lodged in a diverticulum. (5.4)
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (incidence >10%) reported in clinical
`studies with Orenitram are headache, nausea, and diarrhea. (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-------------------------------
`•
`Blood pressure lowering drugs (e.g., diuretics, antihypertensive
`agents, or vasodilators): Risk of hypotension (7.1)
`• When co-administered with strong CYP2C8 inhibitors the initial
`dose is 0.125 mg BID with 0.125 mg BID dose increments every 3
`to 4 days. (7.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1. INDICATIONS AND USAGE
`1.1 Pulmonary Arterial Hypertension
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Interruptions and Discontinuation
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Worsening PAH Symptoms upon Abrupt Withdrawal
`5.2 Risk of Bleeding
`5.3 Increased Exposure with Alcohol
`5.4 Use in Patients with Blind-end Pouches
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 Antihypertensive Agents or Other Vasodilators
`7.2 Anticoagulants
`7.3 Effect of CYP2C8 Inhibitors
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`
`Revised: 12/2013
`
`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
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Clinical Trials in Pulmonary Arterial Hypertension
`(PAH)
`16 HOW SUPPLIED / STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescr bing information
`are not listed
`
`Reference ID: 3426495
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`

`

`
`
`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 improve exercise capacity. The study that established effectiveness included predominately
`patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH
`(75%) or PAH associated with connective tissue disease (19%).
`
`When used as the sole vasodilator, the effect of Orenitram on exercise is about 10% of the deficit,
`and the effect, if any, on a background of another vasodilator is probably less than this. Orenitram
`is probably most useful to replace subcutaneous, intravenous, or inhaled treprostinil, but this use
`has not been studied.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`Orenitram is supplied as extended release tablets. Individualize dosing of Orenitram according to
`clinical response.
`
`The recommended starting dose of Orenitram is 0.25 mg twice daily (BID) with food, taken
`approximately 12 hours apart. Increase the dose as tolerated to achieve optimal clinical
`response. The recommended increment is 0.25 or 0.5 mg BID every 3-4 days. If 0.25 mg BID
`dose increments are not tolerated consider titrating slower. The total daily dose can be divided
`and given three times daily with food (TID; approximately 8 hours apart), titrating by increments of
`0.125 mg TID.
`
`The maximum dose is determined by tolerability. The mean dose in a controlled clinical trial at 12
`weeks was 3.4 mg BID. Maximum doses studied were 12 mg BID in the 12-week blinded study
`and up to 21 mg BID in an open-label long-term study.
`
`If intolerable pharmacologic effects occur, decrease the dose in increments of 0.25 mg. Avoid
`abrupt discontinuation [see Warnings and Precautions (5.1)].
`
`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 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) [see Contraindications (4), Warnings and
`Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
`
`Concomitant administration 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 every 3 to 4 days.
`
`Take Orenitram with food. Swallow Orenitram intact; use only intact tablets.
`
`2.2 Interruptions and Discontinuation
`If a dose of medication is missed, 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 divide the oral total daily
`dose by 5.
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`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) is available in the following four 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]
`
`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 Risk of Bleeding
`Orenitram inhibits platelet aggregation and increases the risk of bleeding.
`
`5.3 Increased Exposure with Alcohol
`Do not take Orenitram with alcohol as release of treprostinil from the tablet may occur at a faster
`rate than intended.
`
`5.4 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), the most commonly reported adverse reactions that occurred in patients receiving Orenitram
`included: headache, nausea, and diarrhea. Table 1 lists the adverse reactions that occurred at a
`rate on Orenitram at least 5% higher than on placebo.
`
`Orenitram patients in Table 1 for Study 1 (N = 151) had access to 0.25 mg tablets at
`randomization. Approximately 91% of such patients experienced an adverse reaction, but only
`4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). The
`overall discontinuation rate for any reason was 17% for active and 14% for placebo.
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`Table 1: Adverse Reactions with Rates at Least 5% Higher on Orenitram Monotherapy than
`on Placebo
`Reaction
`
`Orenitram
`N=151
`
`Placebo
`N=77
`
`Headache
`
`Diarrhea
`
`Nausea
`
`Flushing
`
`Pain in jaw
`
`Pain in extremity
`
`Hypokalemia
`
`Abdominal discomfort
`
`
`
`63%
`
`30%
`
`30%
`
`15%
`
`11%
`
`14%
`
`9%
`
`6%
`
`19%
`
`16%
`
`18%
`
`6%
`
`4%
`
`8%
`
`3%
`
`0%
`
`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.
`
`7 DRUG INTERACTIONS
`7.1 Antihypertensive Agents or Other Vasodilators
`Concomitant administration of Orenitram with diuretics, antihypertensive agents or other
`vasodilators increases the risk of symptomatic hypotension.
`
`7.2 Anticoagulants
`Treprostinil inhibits platelet aggregation; there is increased risk of bleeding, particularly among
`patients receiving anticoagulants.
`
`7.3 Effect of CYP2C8 Inhibitors
`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 every 3 to 4 days [see Dosage and Administration (2.1)
`and Clinical Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C.
`
`Animal reproductive studies with treprostinil diolamine have shown an adverse effect on the fetus.
`There are no adequate and well-controlled studies in humans.
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`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 10- (male) to 18-
`(female) fold the usual human exposure at the mean dose of 3.4 mg BID.
`
`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 represent 13 and 55 times, respectively, the human exposure.
`
`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 or 6 times the human exposure.
`
`In pregnant rabbits, the primary maternal adverse effects were 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 5 times the human
`exposure.
`
`8.2 Labor and Delivery
`The effect of Orenitram on labor and delivery in humans is unknown. No treprostinil treatment-
`related effects on labor and delivery were seen in animal studies.
`
`8.3 Nursing Mothers
`It is not known whether treprostinil is excreted in human milk or absorbed systemically after
`ingestion. Because many drugs are excreted in human milk, choose Orenitram or breastfeeding.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`8.5 Geriatric Use
`Clinical studies of Orenitram did not include sufficient numbers of patients aged 65 years and
`over to determine whether they respond differently from 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.
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`8.6 Patients with Hepatic lmpairrnent
`
`There is a marked increase in the systemic exposure to treprostinil in hepatically impaired
`patients [see Dosage and Administration (2.1), 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)].
`
`10 OVERDOSAGE
`
`Signs and symptoms of overdose with Orenitram during clinical trials reflect its dose-limiting
`phannacologic 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-
`hydroxyoctyI]-1H-benz[f]inden-5-yl]oxy]—, complexed with 2,2'-iminobis[ethanol] (1:1). The
`molecular formula is CBHMO5.C4H"N02, the molecular weight is 495.65, and it has the following
`structural formula:
`
`oAcozH
`
`CH3
`
`HO\/\N/\/OH
`H
`
`Orenitram tablets are formulated in four 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), or 2.5 mg
`of treprostinil (equivalent to 3.17 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 imprinting ink contains
`shellac glaze, ethanol, isopropyl alcohol USP, iron oxide black, n-butyl alcohol, propylene glycol,
`and ammonium hydroxide.
`
`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-penneable 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-penneable 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 out through the tablet at a controlled
`rate.
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`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.
`
`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 of 0.5 and 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.
`
`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.
`
`Distribution
`The treprostinil component of Orenitram is highly bound to human plasma proteins, approximately
`96% over a treprostinil concentration range of 0.01-10 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 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 (7.3)].
`
`Special 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,
`respectively values seen in healthy subjects. 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 (2.1), Contraindications (4), and Use in Specific Populations (8.6)].
`
`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 AUC 0-inf
`that was not significantly altered compared to healthy subjects.
`
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`
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`Drug Interactions
`
`Results of drug interaction studies are shown in Figure 1. Only for the strong CYP2C8 inhibitor
`does the interaction affect dosing.
`
`Figure 1: Impact of Co-Administered Drugs on the Systemic Exposure of Treprostinil 1 mg
`Compared to Orenitram Administered Alone
`
`
`
`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.
`
`
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`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`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. The exposures obtained at the highest dose levels used in males and
`females are about 8- and 17-fold, respectively, the human exposure at the mean dose of 3.4 mg
`BID.
`
`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.
`
`No adverse effect doses for fertility, fetal viability / growth, fetal development (teratogenicity), and
`postnatal development were determined in rats. In pregnant rabbits, external fetal and soft tissue
`malformations and fetal skeletal malformation occurred with the no observed adverse effect level
`for these adverse effects of 0.5 mg/kg/day (5 times the human exposure) [see Use in Specific
`Populations (8.1)].
`
`14 CLINICAL STUDIES
`14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
`Three multi-center, randomized, double-blind studies were conducted and compared oral
`Orenitram to placebo in a total of 349 (Study 1), 350 (Study 2), and 310 (Study 3) 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.
`
`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 6MWD by
`approximately +23 meters (Hodges-Lehmann estimate; p=0.013, non-parametric analysis of
`covariance in accordance with the pre-specified statistical analysis plan) 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. The distribution of the 6MWD change from baseline at Week 12 was also plotted
`across the range of observed values (Figure 3).
`
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`Figure 2: Hodges-Lehmann Estimate of Treatment Effect by Visit for the Primary Analysis
`Population (Study 1)
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`Figure 3: Plot of the Distribution of Peak 6MWD Changes at Week 12 for the Primary
`Analysis Population (Study 1)
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`The placebo-corrected median treatment effect on 6MWD was estimated (using the Hodges
`Lehmann estimator) within various subpopulations defined by age, gender, disease etiology, and
`baseline 6MWD (Figure 4).
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`Figure 4: Placebo Corrected Median Treatment Effect (Hodges-Lehmann estimate with 95%
`CI) on 6MWD Change from Baseline at Week 12 for Various Subgroups in the Primary
`Analysis Population (Study 1)
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`Studies 2 and 3 (no effect on a background of ERA, PDE5 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 PDE5
`inhibitor. The results did not demonstrate a benefit in exercise testing with median 6MWD at
`Week 16 (11 meters [Hodges-Lehmann estimate; p=0.072] and 10 meters [Hodges-Lehmann
`estimate; p=0.089], respectively).
`
`Long-Term Treatment of Pulmonary Hypertension
`Patients (N=824) from the placebo-controlled studies entered a long-term, uncontrolled, open-
`label extension study. The average exposure to Orenitram was approximately 2 years with a
`maximum exposure of approximately 6 years. The dose of Orenitram continued to increase over
`time with doses (mean ± SD) of 3.6 ± 2.7, 4.1 ± 3.1, and 5 ± 3.7 mg BID at 6 (n=649), 12 (n=433),
`and 24 months (n=238), respectively. Reasons for discontinuation from the study included
`adverse event (16%), progression of disease (15%), death (13%), and withdrawn consent (7%).
`In the 522 subjects that completed the 12-month efficacy assessment, their mean 6MWD
`improved by 24 meters compared to baseline (30 meters in monotherapy patients and 20 meters
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`when Orenitram was used in combination with an ERA and/or a PDE-5 inhibitor). Of the patients
`that remained in the study, overall survival was 92%, 87%, and 82% at the end of 1, 2, and 3-
`years, respectively, with progression-free survival (progression defined as death, discontinuation
`or addition of a PAH therapy) of 74%, 61%, and 47%. Without a control group, these data must
`be interpreted cautiously.
`
`16 HOW SUPPLIED / STORAGE AND HANDLING
`16.1 How Supplied
`Orenitram is a 7 mm round biconvex tablet with strength identifying color and printing and
`supplied as follows:
`
`Strength
`
`Color
`
`0.125 mg
`0.25 mg
`1 mg
`2.5 mg
`
`
`
`White
`Green
`Yellow
`Pink
`
`Printing on
`Tablets
`UT 0.125
`UT 0.25
`UT 1
`UT 2.5
`
`NDC #
`Bottle/100
`66302-300-01
`66302-302-01
`66302-310-01
`66302-325-01
`
`16.2 Storage
`Store at 25°C (77°F); excursions 15°C to 30°C (59°F to 86°F) [See USP controlled room
`temperature]. Keep out of reach of children.
`
`17 PATIENT COUNSELING INFORMATION
`See FDA-approved patient labeling (Patient Package Insert).
`
`Tell patients:
`• Abrupt discontinuation of therapy could result in worsening of PAH symptoms.
`• Take Orenitram with food.
`• Swallow Orenitram tablets whole. Do not split, chew, crush, or break. Do not take a tablet
`that is damaged or broken.
`• The biologically inert components of the tablet remain intact during gastrointestinal transit
`and are eliminated in the feces as an insoluble shell.
`• Do not take Orenitram with alcohol.
`
`
`
`Copyright 2013 United Therapeutics Corp. All rights reserved.
`
`Orenitram manufactured for:
`United Therapeutics Corp.
`Research Triangle Park, NC 27709
`
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`Patient Information
`Orenitram (oh-REN-i-tram)
`(treprostinil)
`Extended Release Tablets
`
`What is Orenitram?
`Orenitram is a prescription medicine used to treat pulmonary arterial hypertension (PAH) which
`is high blood pressure in the arteries of your lungs. Orenitram may improve your ability to
`exercise.
`It is not known if Orenitram is safe and effective in children under 18 years of age.
`
`Who should not take Orenitram?
`Do not take Orenitram if you have severe liver problems.
`
`What should I tell my healthcare provider before taking Orenitram?
`Before you take Orenitram, tell your healthcare provider if you:
`• have liver problems
`• have low blood pressure or high blood pressure
`• have had a stroke
`• have stomach ulcers
`• have diverticulosis
`• have any other medical conditions
`• are pregnant or plan to become pregnant. It is not known if Orenitram will harm your unborn
`baby.
`• are breastfeeding or plan to breastfeed. It is not known if Orenitram passes into your breast
`milk. You and your healthcare provider should decide if you will take Orenitram or breastfeed.
`You should not do both.
`Tell your healthcare provider about all the medicines you take, including prescription and
`over-the-counter medicines, vitamins, and herbal supplements. Orenitram and other medicines
`may affect each other causing side effects. Do not start any new medicine until you check with
`your healthcare provider.
`Especially tell your healthcare provider if you take another medicine that contains treprostinil,
`such as Remodulin or Tyvaso.
`Know the medicines you take. Keep a list of them to show to your healthcare provider and
`pharmacist when you get a new medicine.
`
`How should I take Orenitram?
`• Take Orenitram exactly as your healthcare provider tells you to take it.
`• Your healthcare provider will slowly increase your dose to find the dose of Orenitram that is
`right for you.
`• Do not change your dose or suddenly stop taking Orenitram without first talking to
`your healthcare provider. Stopping Orenitram suddenly may cause worsening of
`your PAH symptoms.
`• Orenitram is usually taken every 12 h