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` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
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`ORENITRAM® safely and effectively. See Full Prescribing
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`Information for ORENITRAM.
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`ORENITRAM (treprostinil) extended-release tablets, for oral use
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`Initial U.S. Approval: 2002
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`--------------------------- INDICATIONS AND USAGE----------------------------
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`Orenitram is a prostacyclin vasodilator indicated for:
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`Treatment of pulmonary arterial hypertension (PAH) (WHO
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`Group 1) to improve exercise capacity. The study that
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`established effectiveness included predominately patients with
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`WHO functional class II-III symptoms and etiologies of idiopathic
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`or heritable PAH (75%) or PAH associated with connective tissue
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`disease (19%). (1.1)
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`As the sole vasodilator, the effect on exercise is small. Orenitram has
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`not been shown to add to other vasodilator therapy. (1.1)
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`•
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`-----------------------DOSAGE AND ADMINISTRATION ----------------------
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`• Give with food. Swallow tablets whole; use only intact tablets.
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`(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
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`every 3 to 4 days as tolerated. (2.1)
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`• Maximum dose is determined by tolerability. (2.1)
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`• Mild hepatic impairment (Child Pugh Class A): Initiate at 0.125
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`mg BID. Increment at 0.125 mg BID every 3 to 4 days. (2.2)
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`Avoid use in patients with moderate hepatic impairment. (2.2)
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`•
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`------------------------------ CONTRAINDICATIONS -----------------------------
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`Severe hepatic impairment (Child Pugh Class C). (4)
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`•
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`----------------------- WARNINGS AND PRECAUTIONS ----------------------
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`Do not abruptly discontinue dosing. (2.2, 5.1)
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`Increased risk of bleeding, particularly in patients receiving
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`anticoagulants. (5.2)
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`Do not take Orenitram with alcohol (5.3)
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`In patients with diverticulosis Orenitram tablets can become
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`lodged in a diverticulum. (5.4)
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`------------------------------ ADVERSE REACTIONS -----------------------------
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`Most common adverse reactions (incidence >10%) reported in clinical
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`studies with Orenitram are headache, nausea, and diarrhea. (6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact United
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`Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088
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`or www.fda.gov/medwatch.
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`------------------------------ DRUG INTERACTIONS------------------------------
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`Blood pressure lowering drugs (e.g., diuretics, antihypertensive
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`agents, or vasodilators): Risk of hypotension (7.1)
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`• When co-administered with strong CYP2C8 inhibitors the initial
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`dose is 0.125 mg BID with 0.125 mg BID dose increments every
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`3 to 4 days. (2.3, 7.3)
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`See 17 for PATIENT COUNSELING INFORMATIONand FDA-
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` Revised: 10/2014
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`10 OVERDOSAGE ..................................................................6
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`11 DESCRIPTION....................................................................6
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`12 CLINICAL PHARMACOLOGY ...........................................7
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`12.1 Mechanism of Action ....................................................7
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`12.2 Pharmacodynamics......................................................7
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`12.3 Pharmacokinetics .........................................................7
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`13 NONCLINICAL TOXICOLOGY...........................................9
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility ..9
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`14 CLINICAL STUDIES ...........................................................9
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`14.1 Clinical Trials in Pulmonary Arterial Hypertension
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`(PAH) ...................................................................................9
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`16 HOW SUPPLIED / STORAGE AND HANDLING .............13
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`16.1 How Supplied .............................................................13
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`16.2 Storage ......................................................................13
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`17 PATIENT COUNSELING INFORMATION ........................13
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`*Sections or subsections omitted from the full prescribing information
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`are not listed
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`--------------------- DOSAGE FORMS AND STRENGTHS---------------------
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`Extended-Release Tablets: 0.125 mg, 0.25 mg, 1 mg and 2.5 mg. (3)
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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` 1. INDICATIONS AND USAGE................................................2
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`1.1 Pulmonary Arterial Hypertension ....................................2
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`2 DOSAGE AND ADMINISTRATION ......................................2
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`2.1 Recommended Dosing ...................................................2
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`2.2 Hepatic Impairment ........................................................2
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`2.3 Concomitant Administration with CYP2C8 Inhibitors ......2
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`2.4 Interruptions and Discontinuation ...................................2
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`3 DOSAGE FORMS AND STRENGTHS .................................3
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`4 CONTRAINDICATIONS ........................................................3
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`5 WARNINGS AND PRECAUTIONS.......................................3
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`5.1 Worsening PAH Symptoms upon Abrupt Withdrawal .....3
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`5.2 Risk of Bleeding .............................................................3
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`5.3 Increased Exposure with Alcohol ...................................3
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`5.4 Use in Patients with Blind-end Pouches .........................3
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`6 ADVERSE REACTIONS .......................................................3
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`6.1 Clinical Trials Experience ...............................................3
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`7 DRUG INTERACTIONS ........................................................4
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`7.1 Antihypertensive Agents or Other Vasodilators ..............4
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`7.2 Anticoagulants ................................................................4
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`7.3 Effect of CYP2C8 Inhibitors ............................................4
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`8 USE IN SPECIFIC POPULATIONS ......................................4
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`8.1 Pregnancy ......................................................................4
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` 8.2 Labor and Delivery .........................................................5
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`8.3 Nursing Mothers .............................................................5
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`8.4 Pediatric Use ..................................................................5
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`8.5 Geriatric Use ..................................................................5
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`8.6 Patients with Hepatic Impairment ...................................6
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`8.7 Patients with Renal Impairment ......................................6
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`Reference ID: 3640130
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`FULL PRESCRIBING INFORMATION
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`1. INDICATIONS AND USAGE
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`1.1 Pulmonary Arterial Hypertension
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`Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1)
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`to improve exercise capacity. The study that established effectiveness included predominately
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`patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH
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`(75%) or PAH associated with connective tissue disease (19%).
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`When used as the sole vasodilator, the effect of Orenitram on exercise is about 10% of the deficit,
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`and the effect, if any, on a background of another vasodilator is probably less than this. Orenitram
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`is probably most useful to replace subcutaneous, intravenous, or inhaled treprostinil, but this use
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`has not been studied.
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Recommended Dosing
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`Individualize dosing of Orenitram according to clinical response.
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`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
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`approximately 12 hours apart or 0.125 mg three times daily (TID) with food, taken approximately
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`8 hours apart. Increase the dose as tolerated to achieve optimal clinical response. The
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`recommended increment is 0.25 or 0.5 mg BID or 0.125 mg TID every 3-4 days. If dose
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`increments are not tolerated consider titrating slower.
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`The maximum dose is determined by tolerability. The mean dose in a controlled clinical trial at 12
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`weeks was 3.4 mg BID. Maximum doses studied were 12 mg BID in the 12-week blinded study
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`and up to 21 mg BID in an open-label long-term study.
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`If intolerable pharmacologic effects occur, decrease the dose in increments of 0.25 mg. Avoid
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`abrupt discontinuation [see Warnings and Precautions (5.1)].
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`2.2 Hepatic Impairment
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`In patients with mild hepatic impairment (Child Pugh Class A) start at 0.125 mg BID with 0.125
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`mg BID dose increments every 3 to 4 days. Avoid use of Orenitram in patients with moderate
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`hepatic impairment (Child Pugh Class B). Orenitram is contraindicated in patients with severe
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`hepatic impairment (Child Pugh Class C) [see Contraindications (4), Warnings and Precautions
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`(5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
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`2.3 Concomitant Administration with CYP2C8 Inhibitors
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`When co-administered with strong CYP2C8 inhibitors (e.g., gemfibrozil) the initial dose is 0.125
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`mg BID with 0.125 mg BID dose increments every 3 to 4 days.
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`2.4 Interruptions and Discontinuation
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`If a dose of medication is missed, the patient should take the missed dose as soon as possible,
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`with food. If a patient misses two or more doses, restart at a lower dose and re-titrate.
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`In the event of a planned short-term treatment interruption for patients unable to take oral
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`medications, consider a temporary infusion of subcutaneous or intravenous treprostinil. To
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`calculate the total daily dose (mg) of treprostinil for the parenteral route divide the oral total daily
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`dose by 5.
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`2
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`Reference ID: 3640130
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`When discontinuing Orenitram, reduce the dose in steps of 0.5 to 1 mg per day [see Warnings
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`and Precautions (5.1)].
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`3 DOSAGE FORMS AND STRENGTHS
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`Orenitram (treprostinil extended-release) is available in the following four strengths:
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`- 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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`- 2.5 mg [Pink tablet imprinted with UT 2.5]
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`4 CONTRAINDICATIONS
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`Severe hepatic impairment (Child Pugh Class C) [see Use In Specific Populations (8.6) and
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`Clinical Pharmacology (12.3)].
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Worsening PAH Symptoms upon Abrupt Withdrawal
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`Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in
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`worsening of PAH symptoms.
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`5.2 Risk of Bleeding
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`Orenitram inhibits platelet aggregation and increases the risk of bleeding.
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`5.3 Increased Exposure with Alcohol
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`Do not take Orenitram with alcohol as release of treprostinil from the tablet may occur at a faster
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`5.4 Use in Patients with Blind-end Pouches
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`The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
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`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
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`another drug and may not reflect the rates observed in clinical practice.
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`In a 12-week placebo-controlled monotherapy study (Study 1; WHO Group 1; functional class II-
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`III), the most commonly reported adverse reactions that occurred in patients receiving Orenitram
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`included: headache, nausea, and diarrhea. Table 1 lists the adverse reactions that occurred at a
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`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
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`randomization. Approximately 91% of such patients experienced an adverse reaction, but only
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`4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). The
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`overall discontinuation rate for any reason was 17% for active and 14% for placebo.
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`Reference ID: 3640130
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`Table 1: Adverse Reactions with Rates at Least 5% Higher on Orenitram Monotherapy than
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`on Placebo
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` Orenitram
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` N=151
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` Placebo
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` N=77
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` Headache
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` Diarrhea
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` Nausea
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` Flushing
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` Pain in jaw
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` Pain in extremity
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` Hypokalemia
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` Abdominal discomfort
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` 63%
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` 30%
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` 30%
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` 15%
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` 11%
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` 14%
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` 9%
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` 6%
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` 19%
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` 16%
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` 18%
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` 6%
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` 4%
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` 8%
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`Orenitram was studied in a long-term, open-label extension study in which 824 patients were
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`dosed for a mean duration of approximately 2 years. About 70% of patients continued treatment
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`with Orenitram for at least a year. The mean dose was 4.2 mg BID at one year. The adverse
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`reactions were similar to those observed in the placebo-controlled trials.
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`7 DRUG INTERACTIONS
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`7.1 Antihypertensive Agents or Other Vasodilators
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`Concomitant administration of Orenitram with diuretics, antihypertensive agents or other
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`vasodilators increases the risk of symptomatic hypotension.
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`7.2 Anticoagulants
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`Treprostinil inhibits platelet aggregation; there is increased risk of bleeding, particularly among
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`patients receiving anticoagulants.
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`7.3 Effect of CYP2C8 Inhibitors
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`Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil in healthy adult
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`volunteers increases exposure to treprostinil. Reduce the starting dose of Orenitram to 0.125 mg
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`BID and use 0.125 mg BID increments every 3 to 4 days [see Dosage and Administration (2.3)
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`and Clinical Pharmacology (12.3)].
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`Pregnancy Category C.
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`Animal reproductive studies with treprostinil diolamine have shown an adverse effect on the fetus.
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`There are no adequate and well-controlled studies in humans.
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`4
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`Reference ID: 3640130
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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-
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`(female) fold the usual human exposure at the mean dose of 3.4 mg BID.
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`In pregnant rats, reversible, dose-dependent decreases in body weight gain and food
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`consumption were observed during the first four days of dosing in animals administered 10, 20
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`and 30 mg/kg/day treprostinil diolamine. In a dose range-finding study, there was a 17%
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`decrease in the pregnancy rate in the animals administered 20 and 30 mg/kg/day. One dam in
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`each of the 20 and 30 mg/kg/day had litters with no viable fetuses. In the definitive study (0, 5, 10
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`and 20 mg/kg/day), there were four treatment-related deaths, and a 32% decrease in the
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`pregnancy rate for rats administered 20 mg/kg/day. There was an 8% decrease in the pregnancy
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`rate in the animals administered 10 mg/kg/day. Across both studies, an increase in post-
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`implantation loss was observed in animals administered 10 to 30 mg/kg/day, and a significant
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`decrease in the mean number of live births was seen at dose levels ≥10 mg/kg/day. The no
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`observed adverse effect level was 5 mg/kg/day (maternal, fetal viability and growth), and
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`20 mg/kg/day (teratogenicity), the highest dose tested in the definitive study. The exposures at 5
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`and 20 mg/kg/day doses represent 13 and 55 times, respectively, the human exposure.
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`For F1 progeny, a decreased copulation index was observed at the 5 and 10 mg/kg/day
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`treprostinil diolamine dose levels in rats. The no observed effect levels for physical development,
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`reflex development, exploratory behavior, learning and memory, and sexual maturation was
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`10 mg/kg/day. The no observed effect level for F1 progeny general development (based on body
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`weight) was 10 mg/kg/day for females and ≤ 2.5 mg/kg/day for males; the no observed effect
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`level for F1 reproductive performance was 2.5 mg/kg/day or 6 times the human exposure.
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`In pregnant rabbits, the primary maternal adverse effects were gastrointestinal disturbance; dose-
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`dependent decreases in mean body weight, body weight gain, and food consumption were
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`observed. During the post-dose phase, the effect was reversed. In a dose range-finding study,
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`there was a 17% decrease in the pregnancy rate for animals administered 4 mg/kg/day. A dose-
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`dependent increase in post-implantation loss was observed. Two dams administered
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`4 mg/kg/day had litters with no viable fetuses; the mean fetal weight was slightly decreased in
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`animals administered 4 mg/kg/day. In the definitive study, mean fetal weights were significantly
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`decreased in animals administered 0.5 to 3 mg/kg/day of treprostinil diolamine. At doses of 1.5
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`and 3 mg/kg/day, external fetal and soft tissue malformations were observed in a few fetuses,
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`and the total fetal skeletal malformations were significantly increased. The no observed adverse
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`effect level was less than 0.5 mg/kg/day (maternal), 1.5 mg/kg/day (fetal viability and growth), and
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`0.5 mg/kg/day (teratogenicity). The 0.5 mg/kg/day dose represents about 5 times the human
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`exposure.
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`8.2 Labor and Delivery
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`The effect of Orenitram on labor and delivery in humans is unknown. No treprostinil treatment-
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`related effects on labor and delivery were seen in animal studies.
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`8.3 Nursing Mothers
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`It is not known whether treprostinil is excreted in human milk or absorbed systemically after
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`ingestion. Because many drugs are excreted in human milk, choose Orenitram or breastfeeding.
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`8.4 Pediatric Use
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`Safety and effectiveness in pediatric patients have not been established.
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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
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`over to determine whether they respond differently from younger patients. In general, dose
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`selection for an elderly patient should be cautious, reflecting the greater frequency of decreased
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`hepatic or cardiac function, and of concomitant disease or other drug therapy.
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`5
`
`Reference ID: 3640130
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`8.6 Patients with Hepatic Impairment
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`There is a marked increase in the systemic exposure to treprostinil in hepatically impaired
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`patients [see Dosage and Administration (2.2), Contraindications (4), and Clinical Pharmacology
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`(12.3)].
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`8.7 Patients with Renal Impairment
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`No dose adjustments are required in patients with renal impairment. Orenitram is not removed by
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`dialysis [see Clinical Pharmacology (12.3)].
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`10 OVERDOSAGE
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`Signs and symptoms of overdose with Orenitram during clinical trials reflect its dose-limiting
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`pharmacologic effects and include severe headache, nausea, vomiting, diarrhea, and
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`hypotension. Treat supportively.
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`11 DESCRIPTION
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`Orenitram is an extended release osmotic tablet for oral administration. Orenitram is formulated
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`as the diolamine salt of treprostinil, a tricyclic benzindene analogue of prostacyclin. The chemical
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`name is Acetic acid, 2-[[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-
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`hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]-, complexed with 2,2’-iminobis[ethanol] (1:1). The
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`molecular formula is C23H34O5.C4H11NO2, the molecular weight is 495.65, and it has the following
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`structural formula:
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`O
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`CO2H
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`OH
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`NH
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`HO
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`.
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`CH3
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`H
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`H
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`HO
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`H
`H
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`HO
`H
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`Orenitram tablets are formulated in four strengths, which contain 0.125 mg of treprostinil
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`(equivalent to 0.159 mg treprostinil diolamine), 0.25 mg of treprostinil (equivalent to 0.317 mg
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`treprostinil diolamine), 1 mg of treprostinil (equivalent to 1.27 mg treprostinil diolamine), or 2.5 mg
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`of treprostinil (equivalent to 3.17 mg treprostinil diolamine). The formulations also contain xylitol,
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`maltodextrin, sodium lauryl sulfate, magnesium stearate, cellulose acetate, triethyl citrate,
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`polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. In addition tablets may contain
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`colorants FD&C Blue #2, iron oxide yellow, and iron oxide red. The imprinting ink contains
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`shellac glaze, ethanol, isopropyl alcohol USP, iron oxide black, n-butyl alcohol, propylene glycol,
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`and ammonium hydroxide.
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`Orenitram is designed to release treprostinil at a near zero-order rate using an osmotic tablet
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`technology. The tablet core is coated with a semi-permeable membrane and has a laser-drilled
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`aperture through the membrane. Upon contact with water (e.g., after ingestion), the core tablet
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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
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`pressure within the membrane, eventually forcing the drug out through the tablet at a controlled
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`rate.
`
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`6
`
`Reference ID: 3640130
`
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
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`The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic
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`arterial vascular beds, inhibition of platelet aggregation, and inhibition of smooth muscle cell
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`proliferation.
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`12.2 Pharmacodynamics
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`In a clinical trial of 240 healthy adult volunteers, single doses of inhaled treprostinil 54 µg (the
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`target clinical dose) and 84 µg (supratherapeutic inhalation dose) prolonged the corrected QTc
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`interval by approximately 10 msec. The QTc effect dissipated rapidly as the concentration of
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`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
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`(AUC0-t) over the dose range of 0.5 and 15 mg BID. Upon repeat administration with a BID
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`regimen, the accumulation in the systemic exposures to treprostinil is minimal and results in a
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`peak-to-trough ratio of approximately 7. However, a TID regimen will reduce the peak-to-trough
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`fluctuations to approximately 2.5 for the same total daily dose.
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`Absorption
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`The absolute oral bioavailability of Orenitram is approximately 17%. Maximum treprostinil
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`concentrations occur between approximately 4 and 6 hours following Orenitram administration.
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`The absorption of Orenitram is affected by food. The AUCinf of treprostinil was increased by 49%
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` and the Cmax was increased by an average of 13% when Orenitram was administered following a
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` high-fat, high-calorie meal compared to fasting conditions in healthy volunteers. The relative
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` bioavailability of treprostinil following oral administration of Orenitram 1 mg is not significantly
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` altered by meal types ranging from 250 to 500 calories in healthy volunteers.
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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
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`metabolized on the side chain of the molecule via oxidation, oxidative cleavage, dehydration, and
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`glucuronic acid conjugation. Treprostinil is primarily metabolized by CYP2C8 and to a lesser
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`extent by CYP2C9. No new metabolites are found upon oral administration compared to
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`parenteral administration of treprostinil. Only 1.13% and 0.19% is excreted as unchanged parent
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`drug in the feces and urine, respectively. Based on in vitro studies treprostinil does not inhibit or
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`induce major CYP enzymes [see Drug Interactions (7.3)].
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`Special Populations
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`Hepatic Impairment: In subjects with mild (n=8) hepatic impairment, administration of a single 1
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`mg dose of Orenitram resulted in a mean Cmax and an AUC0-inf that were 1.6- and 2.1-fold,
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`respectively values seen in healthy subjects. With moderate impairment (n=8), the corresponding
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`ratios were 4.0- and 4.8-fold, and with severe impairment (n=6), they were 4.8- and 7.6-fold [see
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`Dosage and Administration (2.2), 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),
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`administration of a single 1 mg dose of Orenitram pre- and post-dialysis resulted in an AUC 0-inf
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`that was not significantly altered compared to healthy subjects.
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`7
`
`
`Reference ID: 3640130
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`Drug Interactions
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`Results of drug interaction studies are shown in Figure 1. Only for the strong CYP2C8 inhibitor
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`does the interaction affect dosing.
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`Figure 1: Impact of Co-Administered Drugs on the Systemic Exposure of Treprostinil 1 mg
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`Compared to Orenitram Administered Alone
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`Warfarin: A drug interaction study was carried out with Remodulin co-administered with warfarin
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`(25 mg/day) in healthy volunteers. There was no clinically significant effect of either medication
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`on the pharmacokinetics of treprostinil. Additionally, treprostinil did not affect the
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`pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin
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`and the international normalized ratio (INR) in healthy subjects given a single 25 mg dose of
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`warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of
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`10 ng/kg/min.
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`8
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`Reference ID: 3640130
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10 and 20 mg/kg/day in
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`males and 0, 3, 7.5 and 15 mg/kg/day in females daily for 26 weeks did not significantly increase
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`the incidence of tumors. The exposures obtained at the highest dose levels used in males and
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`females are about 8- and 17-fold, respectively, the human exposure at the mean dose of 3.4 mg
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`BID.
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`In vitro genotoxicity studies with high doses of treprostinil did not demonstrate any mutagenic or
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`clastogenic effects. Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did
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`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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`postnatal development were determined in rats. In pregnant rabbits, external fetal and soft tissue
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`malformations and fetal skeletal malformation occurred with the no observed adverse effect level
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`for these adverse effects of 0.5 mg/kg/day (5 times the human exposure) [see Use in Specific
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`Populations (8.1)].
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`14 CLINICAL STUDIES
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`14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
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`Three multi-center, randomized, double-blind studies were conducted and compared Orenitram to
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`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
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`currently receiving PAH therapy. The primary efficacy endpoint was placebo-corrected change in
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`six-minute walk distance (6MWD) from Baseline to Week 12. Study drug dose was titrated to a
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`maximum of 12 mg BID based on clinical response and study drug tolerability. Study 1 enrolled
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`349 patients (overall analysis population) who were not receiving any PAH medication. At the
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`beginning of the study, subjects were dosed with only the 1 mg tablets with 0.5 and 0.25 mg
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`tablets introduced at sequentially later dates during the study. The primary analysis population
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`consisted of the 228 patients who had access to the 0.25 mg tablet at the time of randomization.
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`Patients were administered Orenitram or placebo twice daily, with the doses titrated to effect over
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`the course of the 12-week trial. Patients were in W HO functional class II (~33%) and class III
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`(~66%) with either idiopathic or heritable PAH (~75%), collagen vascular disease associated PAH
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`(~19%), or PAH associated with HIV (1%) or congenital heart defect (5%) or other conditions
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`(~6%). The patients' mean baseline 6MWD was approximately 330 meters. In the primary
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`analysis population, 17% of patients discontinued Orenitram compared to 14% of patients on
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`placebo.
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`The primary efficacy endpoint of the trial was the change in 6MWD at 12 weeks for the primary
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`analysis population. Analysis of Study 1 results demonstrated that those patients receiving
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`Orenitram compared to patients receiving placebo improved their median 6MWD by
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`approximately +23 meters (Hodges-Lehmann estimate; p=0.013, non-parametric analysis of
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`covariance in accordance with the pre-specified statistical analysis plan) as compared to patients
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`receiving placebo as demonstrated in (Figure 2). The within group median change from baseline
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`was +25 meters for Orenitram and -5 meters for placebo at week 12 (N=228). Mean dose (±SD)
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