`
`
`
` 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 --------------------------­
`
`
`
`
`• Dosage and Administration (2.2)
`01/2017
`
`
`
`
`--------------------------- 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)
`
`
`
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`• Starting dose: 0.25 mg BID or 0.125 mg TID. (2.1)
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`
`
`
`
`
`• 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)
`
`
`
`• 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)
`
`
`• Mild hepatic impairment (Child Pugh Class A): Initiate at 0.125 mg
`
`
`
`
`
`BID. Increment at 0.125 mg BID every 3 to 4 days. (2.3)
`
`
`
`
`
`
`• Avoid use in patients with moderate hepatic impairment. (2.3)
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`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` 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 Risk of Bleeding
`
`5.3 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 Antihypertensive Agents or Other Vasodilators
`
`7.2 Anticoagulants
`
`
`7.3 Effect of CYP2C8 Inhibitors
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`Reference ID: 4045427
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`Extended-Release Tablets: 0.125 mg, 0.25 mg, 1 mg, 2.5 mg and
`
`
`
`
`
`5 mg. (3)
`
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------­
`
`
`
`
`• Severe hepatic impairment (Child Pugh Class C). (4)
`
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`
`• Do not abruptly discontinue dosing. (2.5, 5.1)
`
`
`
`
`• Increased risk of bleeding, particularly in patients receiving
`
`anticoagulants. (5.2)
`
`
`• In patients with diverticulosis Orenitram tablets can become lodged
`
`
`
`
`in a diverticulum. (5.3)
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`Most common adverse reactions (incidence >5%) reported in clinical
`
`
`
`
`studies with Orenitram are headache, diarrhea, nausea, 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------------------------------­
`
`
`
`• 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. (2.4, 7.3)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`
`approved patient labeling.
`
`
`Revised: 01/2017
`
`
`
`8.1 Pregnancy
`
`
`8.2 Labor and Delivery
`
`8.3 Nursing Mothers
`
`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
`
`(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 prescribing information
`
` are not listed
`
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1124, p. 1 of 14
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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.
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
` 2.1 Recommended Dosing
` Take Orenitram with food. Swallow Orenitram tablets whole; do not crush, split, or chew.
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
` The recommended starting dose of Orenitram is 0.25 mg twice daily (BID) with food, taken
`
`
`
`
`approximately 12 hours apart or 0.125 mg three times daily (TID) with food, taken approximately
`
`
`
`
`
`
`8 hours apart. Increase the dose to the highest tolerated dose. The recommended increment is
`
`
`
`
`0.25 or 0.5 mg BID or 0.125 mg TID every 3-4 days. If dose increments are not tolerated consider
`
`titrating slower.
`
`
`
`The appropriate maintenance dose is determined by tolerability.
`
`
`
`If intolerable pharmacologic effects occur, decrease the dose in increments of 0.25 mg. 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 comparable total daily dose of Orenitram in mg using a patient’s dose of IV/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 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), 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 every 3 to 4 days.
`
`
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`
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`
`
` 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.
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`Reference ID: 4045427
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`In the event of a planned short-term treatment interruption for patients unable to take oral medications,
`
`
`
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`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 [W hite tablet imprinted with UT 0.125]
`
`
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`- 0.25 mg [Green tablet imprinted with UT 0.25]
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`- 1 mg [Yellow tablet imprinted with UT 1]
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`
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`- 2.5 mg [Pink tablet imprinted with UT 2.5]
`
`
`
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`- 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 Risk of Bleeding
`
`Orenitram inhibits platelet aggregation and increases the risk of bleeding.
`
`
`
`
`5.3 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),
`
`
`
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`the most commonly reported adverse reactions that occurred in patients receiving Orenitram included:
`
`
`
`
`headache, diarrhea, nausea, and flushing. Table 1 lists the most common adverse reactions that
`
`
`
`
`
`occurred at a rate on Orenitram at least 5% higher than on placebo.
`
`
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`Orenitram patients in Table 1 for Study 1 (N = 151) had access to 0.25 mg tablets at randomization.
`
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`
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`Approximately 91% of such patients experienced an adverse reaction, but only 4% discontinued
`
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`
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`therapy for an adverse reaction (compared to 3% receiving placebo). The overall discontinuation rate
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`
`
`for any reason was 17% for active and 14% for placebo.
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`Reference ID: 4045427
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` Table 1:
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`
`
` 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
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`
`
` Pain in jaw
`
`
`
` Pain in extremity
`
`
`
` Hypokalemia
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`
`
` Abdominal discomfort
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`
`
`
` 63%
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`
`
` 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.
`
`
`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 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 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 (2.4) and Clinical
`
`
`
`
`Pharmacology (12.3)].
`
`
`
`
`Reference ID: 4045427
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`8 USE IN SPECIFIC POPULATIONS
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`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
`
`
`
`
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`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
`
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`
`
`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
`
`
`
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`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
`
`
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`10 mg/kg/day. Across both studies, an increase in post-implantation loss was observed in animals
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`
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`administered 10 to 30 mg/kg/day, and a significant decrease in the mean number of live births was
`
`
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`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.
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`
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`For F1 progeny, a decreased copulation index was observed at the 5 and 10 mg/kg/day treprostinil
`
`
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`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
`
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`
`
`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.
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`
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`
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`Reference ID: 4045427
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`8.5 Geriatric Use
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`
`
`
`
`
`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.
`
`
`
`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)].
`
`
`
`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),
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`
`
`
`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
`
`
`
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`diolamine). The formulations also contain xylitol, maltodextrin, sodium lauryl sulfate, magnesium
`
`
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`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.
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`
`
`
`The imprinting ink contains shellac glaze, ethanol, isopropyl alcohol USP, iron oxide black, n-butyl
`
`alcohol, and propylene glycol.
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`
`
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`Orenitram is designed to release treprostinil at a near zero-order rate using an osmotic tablet
`
`
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`
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`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
`
`
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`
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`absorbs water through the semi-permeable membrane. The water dissolves the water-soluble
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`treprostinil diolamine and the water-soluble osmotic excipients, which creates hydrostatic pressure
`
`
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`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.
`
`
`
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`12.3 Pharmacokinetics
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`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,
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`
`
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`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.
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`
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`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.
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`
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`The absorption of Orenitram is affected by food. The AUCinf of treprostinil was increased by 49% and
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`
`
`
`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
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`
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`treprostinil following oral administration of Orenitram 1 mg is not significantly altered by meal types
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`
`
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`ranging from 250 to 500 calories in healthy volunteers.
`
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`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.
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`Distribution
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`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.
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`
`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)].
`
`
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`
`
`
`
` 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, respectively,
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`values seen in healthy subjects. With moderate impairment (n=8), the corresponding ratios were 4.0­
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` 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)].
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` Renal Impairment: In patients with severe renal impairment requiring dialysis (n=8), administration of a
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`
`
`
`
`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)].
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`Figure 1:
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`Impact of Co-Administered Drugs on the Systemic Exposure of Treprostinil
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`
`
`1 mg Compared to Orenitram Administered Alone
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` 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
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`
`
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`
`
` 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. 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. Oral
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`
`
` 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 21- and 29-fold, respectively, the human
`
`
`
` exposure.
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`
`
` 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.
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` No adverse effect doses for fertility, fetal viability / growth, fetal development (teratogenicity), and
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`
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`
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` 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)].
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`
` 14 CLINICAL STUDIES
`
`
`
` 14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
` Three multi-center, randomized, double-blind studies were conducted and compared Orenitram to
`
`
` placebo in a total of 349 (Study 1), 350 (Study 2), and 310 (Study 3) patients with PAH.
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` Study 1 (effect seen with no background vasodilator)
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`Study 1 was a 12-week, randomized (2:1 Orenitram to placebo), double-blind, placebo-controlled,
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`international efficacy and safety study of Orenitram in patients with WHO Group 1 PAH not currently
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`receiving PAH therapy. The primary efficacy endpoint was placebo-corrected change in six-minute walk
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`distance (6MWD) from Baseline to Week 12. Study drug dose was titrated to a maximum of 12 mg BID
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`based on clinical response and study drug tolerability. Study 1 enrolled 349 patients (overall analysis
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`population) who were not receiving any PAH medication. At the beginning of the study, subjects were
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`dosed with only the 1 mg tablets with 0.5 and 0.25 mg tablets introduced at sequentially later dates
`
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`during the study. The primary analysis population consisted of the 228 patients who had access to the
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`0.25 mg tablet at the time of randomization. Patients were administered Orenitram or placebo twice
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`
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`daily, with the doses titrated to effect over the course of the 12-week trial. Patients were in W HO
`
`functional class II (~33%) and class III (~66%) with either idiopathic or heritable PAH (~75%), collagen
`
`
`
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`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.
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`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
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` pre-specified statistical analysis plan) as compared to patients receiving placebo as demonstrated in
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`
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`
` (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
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` ± 1.9, and 3.4 ± 1.9 mg BID at W eeks 4, 8, and 12, respectively, with a maximum dose of 12 mg BID.
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` 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:
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`
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`
`
` Hodges-Lehmann Estimate of Treatment Effect by Visit for the Primary Analysis
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` Population (Study 1)
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`Figure 3:
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`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 (using the Hodges Lehmann
`
`
`
` estimator) within various subpopulations defined by age, gender, disease etiology, and baseline
`
`
` 6MW D (Figure 4).
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` Figure 4:
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`
` Placebo Corrected Median Treatment Effect (Hodges-Lehmann estimate with
`
`
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`
`
`
` 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, PDE-5 inhibitor, or both)
`
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`
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`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
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`
`
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`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%) wit