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Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension

How to Use Orenitram Article

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Educational Material

FREEDOM-EV TRIAL—designed with a composite primary endpoint to assess the effect of Orenitram on time to first clinical worsening event

FREEDOM-EV was an international, multicenter, randomized, double-blind, placebo-controlled, event-driven study

• Patients received Orenitram or placebo starting at 0.125 mg TID and titrated to a maximum dose of 12 mg TID
• Randomization was stratified by type of background therapy and baseline 6MWD

Primary Endpoint

Clinical Assessments Summary

Time to First Adjudicated Clinical Worsening Event:

Selected Secondary Endpoints

Change from baseline measured at week 24:

• Exercise capacity as assessed by 6MWD
• Right ventricle dysfunction as indicated by NT-proBNP
• Symptom improvement as indicated by WHO FC

Vital Status Substudy

• Patients who participated in FREEDOM-EV and agreed to be followed were a part of the vital status substudy

The FREEDOM-EV study population was relatively young and recently diagnosed, with the majority of patients at FC II

Patient Profile in FREEDOM-EV

The majority of patients had idiopathic or heritable PAH (63%)

• 26% had PAH associated with connective tissue disease
• 7% had PAH associated with a congenital heart defect
• 1% had PAH associated with HIV infection
• 3% had PAH from other causes

Primary Endpoint

Impact earlier with Orenitram to delay the time to clinical worsening

Patients on Orenitram were at a higher risk at baseline vs placebo (P=0.0017)

• As part of a post hoc analysis, when adjusted for baseline risk stratification, patients on Orenitram had a 39% reduction in the risk of a clinical worsening event (P=0.0006*; HR=0.61; 95% CI, 0.46-0.81; P=0.0006)
• Using the French methodology
• 25.2% of patients on Orenitram had 0 low-risk factors, 33.2% had 1 low-risk factor, 30.3% had 2 low-risk factors, and 11.3% had 3 low-risk factors
• 17.7% of patients on placebo had 0 low-risk factors, 32.9% had 1 low-risk factor, 28.1% had 2 low-risk factors, and 21.3% had 3 low-risk factors

• P-value was calculated with log-rank test stratified by background PAH therapy and baseline 6MWD category.
• Hazard ratio and 95% CI were calculated with proportional hazard model with treatment, background PAH therapy, and baseline 6MWD as explanatory variables.
• Randomization (1:1) was stratified by type of background therapy (ie, PDE-5i or sGCS vs ERA) and by baseline 6MWD (breakpoint ≤350 m).
• Low-risk status criteria included WHO functional class I/II, 6MWD >440 m, and NT-proBNP <300 pg/mL.

Delayed disease progression

Secondary Endpoints

In FREEDOM-EV, Orenitram demonstrated durable improvements across multiple prognostic risk factors

6MWD

Patients demonstrated statistically significant improvements in 6MWD at weeks 36 and 48

• Change in 6MWD was not statistically significant at week 24

NT-proBNP

Orenitram reduced NT-proBNP, an important indicator of right ventricle dysfunction

• Per protocol, NT-proBNP was not collected at week 48
• Statistically significant reductions in NT-proBNP were seen as early as week 12 (P=0.0002)
• P-value was obtained from the analysis of covariance with change from baseline in log-transformed data in NT-proBNP as the dependent variable, treatment as fixed effect, and log-transformed baseline NT-proBNP as a covariate

WHO FC

Orenitram is the only oral prostacyclin-class therapy that has demonstrated improvements in WHO FC

Vital Status Substudy

Orenitram was associated with a positive impact on survival

Orenitram was associated with a 37% reduction in risk of death vs placebo at study closure (P=0.03)

IMPORTANT SAFETY INFORMATION

Contraindications

• Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.

Warnings and Precautions

• Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
• The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

Adverse Reactions

• In the 12-week, placebo-controlled, monotherapy study, and an event-driven, placebo-controlled, combination therapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, vomiting, flushing, pain in jaw, pain in extremity, hypokalemia, abdominal discomfort, and upper abdominal pain.

Drug Interactions

• Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.

Specific Populations

• Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies with Orenitram in pregnant women.
• It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
• Safety and effectiveness of Orenitram in pediatric patients have not been established.
• Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and relative adverse event rates compared to younger patients. Caution should be used when selecting a dose for geriatric patients.
• There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients.

Please see Full Prescribing Information and Patient Information for Orenitram.

For additional information, call 1-877-UNITHER (1-877-864-8437).

6MWD=6-minute walk distance; CI=confidence interval; HR=hazard ratio; OLE=open-label extension; PAH=pulmonary arterial hypertension.

Reference: 1. Data on file. United Therapeutics Corporation. Research Triangle Park, NC.

Dosing Strategy

Start with Orenitram, oral treprostinil—titrate to achieve the appropriate dose for each patient

5 tablet strengths offer flexibility to titrate to clinical response and tolerability, with no labeled maximum dose

When making treatment decisions, consider the ability to titrate to meet the needs of a progressive disease

TID dosing reduces peak-to-trough fluctuations

Orenitram is available in 5 extended-release dose strengths:

Tablets not shown at actual size.

Dosing Considerations:

• Ability to titrate with no labeled maximum dose
• Titrate 0.125 mg every 3 to 4 days or slower as tolerated
• Available in BID and TID dosing in 5 tablet strengths: 0.125 mg, 0.25 mg, 1.0 mg, 2.5 mg, 5mg
• Each dose should be taken with food
• Orenitram tablets should be swallowed whole; advise patients not to crush, split, or chew
• If dose increments are not tolerated, try slowing or temporarily stopping titration. You can also down-titrate if needed. Avoid abrupt discontinuation

Titrating at 0.125 mg TID ~weekly will allow patients to reach a target dose of 3 mg TID by 6 months

Dose adjustment in patients with hepatic impairment or use with CYP2C8 inhibitors¹

• 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
• When co-administered with strong CYP2C8 inhibitors (eg, gemfibrozil) the initial dose is 0.125 mg BID with 0.125 mg BID dose increments every 3 to 4 days

Potential of TID Dosing

While Orenitram can be administered BID or TID, peak-to-trough fluctuations may be reduced by TID dosing

Using the same total daily dose, a TID regimen may reduce peak-to-trough fluctuations to a ratio of approximately 2.5, compared with 7.0 for BID dosing.¹

Real-world use of Orenitram

• As an oral treatment, Orenitram allows healthcare providers to introduce their patients to the benefits of prostacyclin-class therapy
• 70% of Orenitram patients were prostacyclin naive2*
• Patients can begin treatment as early as WHO FC II and III and titrate as tolerated to clinical effect

Progressive Dosing for PAH

For PAH, a progressive disease, Orenitram offers the ability to dose progressively.

Patients on Orenitram achieved similar exposure to Remodulin (treprostinil) Injection.

*The shaded area was approximated based on the mean ± SD across all time points.
†Data represent mean treprostinil concentrations of patients who received Orenitram TID only.²

Study Design

Pharmacokinetic (PK) comparison was based on mean treprostinil concentration vs. time plots by treatment regimen in the 24-week, multicenter, open-label transition study. Thirty-three WHO Group 1 patients on stable doses of IV/SC treprostinil as well as background therapy with a PDE-5i and/or ERA were enrolled. Patients were WHO FC I or II and hemodynamically stable at baseline, with a cardiac index >2.2 L/m2, RAP<11 mm Hg, and PVR<10 Wood units. The primary endpoint of the study was the safety and tolerability of the transition.^1,2

Safety

• Adverse events were associated mainly with prostacyclin pharmacology
• The adverse reactions were similar to those observed in the placebo-controlled trials¹

Dosing

• The mean Orenitram total daily dose at the end of transition was 27 ± 12 mg compared with a mean Remodulin dose prior to transition of 59 ng/kg/min (range, 25 – 111 ng/kg/min)¹
• Orenitram provides the ability to increase dose to highest tolerated dose

‡Total daily dose.
§TID cohort includes dosing and pharmacokinetic data from 1 patient who discontinued the study prior to week 24 but completed pharmacokinetic assessments prior to discontinuation.
AUC=area under the curve; ERA=endothelin receptor antagonist; FC=functional class; IV=intravenous; PAH=pulmonary arterial hypertension; PDE-5i=phosphodiesterase type 5 inhibitor; PVR=pulmonary vascular resistance; RAP=right arterial pressure; SC=subcutaneous; SD=standard deviation; TID=3 times daily; WHO=World Health Organization.

Side effect management strategies

According to the ACCF/AHA 2009 consensus on PAH, patients should be encouraged to be proactive in the management of their disease and openly communicate in the event of clinical problems.¹

Planning a side effect management strategy can help set patient expectations

• Recommendations to aid in proactive side effect management were assembled using the Delphi process, a structured communication technique that gathered information from a panel of respondents with expertise using Orenitram^2,3
• The Delphi process was used to investigate best practices used by panelists (N=12) for side effect management in patients treated with Orenitram. The survey participants were from 11 centers and had a total patient experience of 206 patients²

Top-scored strategies for side effect management

• Panelists were asked to vote on the final document presenting strategies for side effect management on a scale of strongly disagree (-5) to strongly agree (+5)²
• The following table lists the top-scored strategies (a cutoff of 2.5 was used for major recommendations, as long as the SD was not negative)²

ACCF=American College of Cardiology Foundation; AHA=American Heart Association; PAH=pulmonary arterial hypertension; SD=standard deviation.

References:
1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-1619. 2. Rahaghi FF, Feldman JP, Allen RP, et al. The Delphi process in the creation of a consensus statement for practical use of Orenitram. Poster presented at: American Thoracic Society (ATS) 2015 International Conference; May 15-20, 2015; Denver, CO. 3. Hasson F, Keeney S, McKenna H. Research guidelines for the Delphi survey technique. J Adv Nurs. 2000;32(4):1008-1015. 4. Orenitram [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2016.

Planning for dose discontinuations or short-term interruptions

Short-term interruptions

Managing missed doses:

• 1 missed dose: Instruct your patient to take the missed dose as soon as possible with food
• 2 or more missed doses: Restart treatment at a lower dose and retitrate
  Situations may arise where you need to temporarily interrupt oral therapy and use parenteral therapy. Follow these guidelines to help maintain consistent therapy.
• Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms
• For planned short-term interruption: Consider a temporary infusion of subcutaneous or intravenous Remodulin (treprostinil) Injection

Use the following equation to calculate the total daily dose (ng/kg/min) of Remodulin:

Dose discontinuations:

• For planned discontinuation: Reduce the dose in steps of 0.5 to 1 mg per day

Transitioning to Orenitram

When transitioning stable patients from Remodulin to Orenitram, the following equation can be used to estimate a comparable total daily dose of Orenitram. For more information on transitioning, click here.

 For specific examples of dose conversions, see the table below, which was developed using this equation.

United Therapeutics does not provide medical advice. Transitions from Remodulin should be performed in accordance with the Orenitram Full Prescribing Information and your clinical judgment.

Programs for Your Patients

The Orenitram 90-Day Trial Program

The Orenitram 90-Day Trial Program allows you to assess how your patients tolerate Orenitram. The program is offered at no cost for up to 90 days, and your patients have no obligation to continue taking Orenitram at the end of the trial period.

Consider Orenitram for:

• Patients with low- to intermediate-risk parameters* who are not meeting individual goals¹
• Patients who have adequate time to titrate¹
• Patients who need a prostacyclin-class therapy¹

*At baseline, the majority of patients in the FREEDOM-M overall analysis population (N=349) were FC I/II (38%) or FC III (61%). Median (min, max) 6MWD was 345 m (117 m, 468 m).²
6MWD=6-minute walk distance; FC=functional class; WHO=World Health Organization.

Eligibility for this program is limited to patients with PAH (WHO Group 1) who have never been treated with Orenitram. Patients transitioning from another treprostinil medication are not eligible for this program.
Click here for Terms and Conditions.

To enroll your eligible patients, reach out to your United Therapeutics representative for more information

Important Safety Information for Orenitram

Contraindications

• Orenitram is contraindicated in patients with severe hepatic impairment (Child Pugh Class C)

Warnings and Precautions

• Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms
• Orenitram inhibits platelet aggregation and increases the risk of bleeding
• The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum

Drug Interactions/Specific Populations

• Concomitant administration of Orenitram with diuretics, antihypertensive agents, or other vasodilators increases the risk of symptomatic hypotension
• Orenitram inhibits platelet aggregation; there is an increased risk of bleeding, particularly among patients receiving anticoagulants
• Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients
• Pregnancy Category C. Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies in humans
• 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
• Safety and effectiveness in patients under 18 years of age have not been established
• There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients

Adverse Reactions

• In the 12-week placebo-controlled monotherapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, flushing, pain in jaw, pain in extremity, hypokalemia, and abdominal discomfort

References:
1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-1619. 2. Rahaghi FF, Feldman JP, Allen RP, et al. The Delphi process in the creation of a consensus statement for practical use of Orenitram. Poster presented at: American Thoracic Society (ATS) 2015 International Conference; May 15-20, 2015; Denver, CO. 3. Hasson F, Keeney S, McKenna H. Research guidelines for the Delphi survey technique. J Adv Nurs. 2000;32(4):1008-1015. 4. Orenitram [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2016.