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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.
`
`In the event of a planned short-term treatment interruption for patients unable to take oral
`medications, consider a temporary infusion of subcutaneous or intravenous treprostinil. To
`calculate the total daily dose (mg) of treprostinil for the parenteral route use the following
`equation:
`
`Remodulin (ng/kg/min) = 139 X Orenitram total daily dose 1mg!
`weight (kg)
`
`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
`
`4 CONTRAINDICATIONS
`
`Severe hepatic impairment (Child Pugh Class C) [see Use In Specific Populations (8.6) and
`Clinical Pharmacology (12. 3)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Worsening PAH Symptoms upon Abrupt Withdrawal
`
`Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in
`worsening of PAH symptoms.
`
`5.2 Use in Patients with Blind-end Pouches
`
`The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a
`diverticulum.
`
`Orenitram (treprostinil) extended-release tablets are available in the following five strengths:
`- 0.125 mg [White tablet imprinted with UT 0.125]
`- 0.25 mg [Green tablet imprinted with UT 0.25]
`- 1 mg [Yellow tablet imprinted with UT 1]
`- 2.5 mg [Pink tablet imprinted with UT 2.5]
`- 5 mg [Red tablet imprinted with UT 5]
`
`  
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`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
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`12.2 Pharmacodynamics
`
`In a clinical trial of 240 healthy adult volunteers, single doses of inhaled treprostinil 54 ug (the
`target clinical dose) and 84 pg (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
`(AUG 04) over the dose range from 0.5 to 15 mg BID. Upon repeat administration with a BID
`regimen, the accumulation in the systemic exposures to treprostinil is minimal and results in a
`peak-to-trough ratio of approximately 7. However, a TID regimen will reduce the peak-to-trough
`fluctuations to approximately 2.5 for the same total daily dose.
`
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`In a study conducted in healthy volunteers using [14C] treprostinil, treprostinil was extensively
`metabolized on the side chain of the molecule via oxidation, oxidative cleavage, dehydration, and
`glucuronic acid conjugation. Treprostinil is primarily metabolized by CYP2C8 and to a lesser
`extent by CYP2C9. No new major metabolites are found upon oral administration compared to
`parenteral administration of treprostinil. Only 1.13% and 0.19% is excreted as unchanged parent
`drug in the feces and urine, respectively. Based on in vitro studies, treprostinil does not inhibit or
`induce major CYP enzymes [see Drug Interactions (7. I)] .
`
`Absopption
`
`The absolute oral bioavailability of Orenitram is approximately 17%. Maximum treprostinil
`concentrations occur between approximately 4 and 6 hours following Orenitram administration.
`Time to reach steady-state concentrations for both BID and TID regimens is approximately 1 to
`2 days.
`
`The absorption of Orenitram is affected by food. The AUCinf of treprostinil was increased by
`49% and the Cmax was increased by an average of 13% when Orenitram was administered
`following a high-fat, high-calorie meal compared to fasting conditions in healthy volunteers. The
`relative bioavailability of treprostinil following oral administration of Orenitram 1 mg is not
`significantly altered by meal types ranging from 250 to 500 calories in healthy volunteers.
`
`When Orenitram 1 mg was administered with alcohol at 0.5 mg/kg or the equivalent of 3 servings
`(at the same time, or d: 1 hour relative to alcohol consumption), there was no significant change
`(10% to 20% increase) in the exposure to treprostinil compared to Orenitram administered alone.
`
`Distribution
`
`The treprostinil component of Orenitram is highly bound to human plasma proteins,
`approximately 96% over a treprostinil concentration range of 0.01 to 10 ug/mL.
`
`Metabolism and Excretion
`
`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 Cmx and an AUC om that were 1.6- and 2.1-fold
`values seen in healthy subjects, respectively. With moderate impairment (n=8), the
`corresponding ratios were 4.0- and 4.8-fold, and with severe impairment (n=6), they were
`4.8- and 7.6-fold [see Dosage and Administration (2.3), Contraindications (4), and Use in
`Specific Populations (8. 6)].
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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 change in 6MWD by
`approximately 23 meters (p=0.013) as compared to patients receiving placebo as demonstrated in
`(Figure 2). The within group median change from baseline was +25 meters for Orenitram and
`-5 meters for placebo at Week 12 (N=228). Mean dose (iSD) in the Orenitram group was 2.3 d:
`1.3, 3.2 d: 1.9, and 3.4 d: 1.9 mg BID at Weeks 4, 8, and 12, respectively, with a maximum dose of
`12 mg BID. The distribution of the 6MWD change from baseline at Week 12 was also plotted
`across the range of observed values (Figure 3).
`
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`Estimate of Treatment Effect by Visit for the Primary Analysis Population
`Figure 2:
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`
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`
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`
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`Orenitram
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`
`Plot of the Distribution of Peak 6MWD Changes at Week 12 for the Primary
`Figure 3:
`Analysis Population (Study 1)
`
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`The placebo-corrected median treatment effect on 6MWD was estimated within various
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