Treprostinil Side Effects

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Treprostinil Safety and Efficacy

Treprostinil side effects

The side effects associated with treprostinil may include1:

  • Nausea
  • Vomiting
  • Diarrhea
  • Headache
  • Hypotension
  • Flushing

The side effects seen with treprostinil treatment may vary by patient and method of administration. Please see the Important Safety Information for Orenitram, TYVASO, and Remodulin to learn more about side effects.

Treprostinil provides benefits for patients with PH2-5

Treprostinil treatment has been proven to increase exercise capacity and, in some studies, delay disease progression.2-5

Although treprostinil doses are individualized based on patient tolerability and clinical improvement,6 higher doses of treprostinil are associated with the following outcomes:

  • A decreased risk of hospitalization6
  • An improved 6MWD6

Based on a retrospective analysis of combined data from pivotal subcutaneous and oral treprostinil studies. Both studies were 12 weeks, had the same primary endpoint of 6MWD, studied systemically administered treprostinil monotherapy, and titrated treprostinil to the maximum tolerated dose. Patients were grouped into tertiles based on oral or SC treprostinil dose. Analysis of hospitalization included a total of 1619 patients (SC n=860, oral n=759). 6MWD analysis included a total of 466 patients (SC n=233, oral n=233).6

United Therapeutics offers treprostinil in 3 different forms—oral, inhaled, and pump—each designed to meet different needs.

Treprostinil effect on hemodynamics

Studies have shown that, in some cases, treatment with treprostinil can improve a number of hemodynamic parameters, including PVR and CI.5,7-11 The studies represented below include different patient populations, baseline characteristics, and assessment intervals. These data do not imply efficacy.

OralInhaledSCIV
PVRdecreasedecreaseN/AN/A
PVRIN/Adecreasedecreasedecrease
COincreaseincreaseN/AN/A
CIincreaseincreaseincreaseincrease
mPAP–decreasedecreasedecrease
RAP––decreasedecrease
SvO2––increaseN/A

N/A = Not evaluated in study.

   –   = Not statistically significant.

Study design

Oral Treprostinil

This substudy included 61 patients who volunteered for a right heart catheterization at baseline and week 24, out of 690 patients who participated in the original FREEDOM-EV trial.8*

*Excluded from this analysis (n=6) were those patients with missing or mismatched cardiac output estimates (using indirect Fick or thermodilution methodology) at baseline and week 24.8

Inhaled Treprostinil

In a multicenter, nonrandomized, open-label, single-arm study, the efficacy of inhaled treprostinil† on hemodynamics and exercise capacity, safety, and pharmacokinetics was evaluated in 17 Japanese patients with PAH.9

The initial study lasted 12 weeks, and a 40-week, long-term treatment period was available for patients who wanted to continue taking inhaled treprostinil. Of the 17 patients who participated in the initial study, 16 entered the long-term extension and continued taking inhaled treprostinil until week 52.9

Patients initiated inhaled treprostinil at 3 breaths per session, 4 times daily, with a maximum of 9 breaths per session, 4 times daily. If tolerated, the dosage was gradually increased with a minimal interval of 7 days.9

†Additional parameters measured include WHO FC, NT-proBNP, Borg Dyspnea Score, and an MLWHF QOL questionnaire.9

Parenteral Treprostinil Subcutaneous

In two 12-week, multicenter, randomized, double-blind, placebo-controlled trials, subcutaneous treprostinil infusion was compared to placebo in a total of 470 patients. In the pivotal study, the median change in 6MWD at week 12 (primary endpoint) was +10 m for the SC treprostinil group and 0 m for the placebo group. The mean SC treprostinil dose was 9.3 ng/kg/min at 12 weeks.5,10

Parenteral Treprostinil Intravenous [long-term changes]:

The dose of intravenous treprostinil increased from baseline through week 48 to a mean of 98 ng/kg/min in the de novo group. The initial analysis was a 12-week, prospective, open-label, uncontrolled, multicenter study of continuous IV treprostinil in 16 patients aged 12 to 65 with PAH that was idiopathic (n=8), related to connective tissue disease (n=6), or related to congenital heart disease (n=2). The primary endpoint was change in exercise capacity assessed by the 6MWD test.11

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6MWD=6-minute walk distance; CI=cardiac index; CO=cardiac output; FC=functional class; IV=intravenous; MLWHF=Minnesota Living with Heart Failure; mPAP=mean pulmonary arterial pressure; NT-proBNP=N-terminal pro-B-type natriuretic peptide; PAH=pulmonary arterial hypertension; PH=pulmonary hypertension; PVR=pulmonary vascular resistance; PVRI=pulmonary vascular resistance index; QOL=quality of life; RAP=right atrial pressure; SC=subcutaneous; SvO2=mixed venous oxygen saturation; WHO=World Health Organization.

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SELECT IMPORTANT SAFETY INFORMATION

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  • Orenitram is Contraindicated in patients with severe hepatic impairment (Child Pugh Class C).
  • TYVASO and TYVASO DPI have a Warning and Precaution for patients with low systemic arterial pressure, as either product may produce symptomatic hypotension.
  • Remodulin has a Warning and Precaution for chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter, as they are associated with the risk of blood stream infections (BSI) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.

Please see below for Indication, additional Important Safety Information, and links to the Full Prescribing Information for Orenitram, TYVASO, TYVASO DPI, and Remodulin.

SELECT IMPORTANT SAFETY INFORMATION

  • Orenitram is Contraindicated in patients with severe hepatic impairment (Child Pugh Class C).
  • TYVASO and TYVASO DPI have a Warning and Precaution for patients with low systemic arterial pressure, as either product may produce symptomatic hypotension.
  • Remodulin has a Warning and Precaution for chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter, as they are associated with the risk of blood stream infections (BSI) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.

Please see below for Indication, Important Safety Information, and links to the Full Prescribing Information for Orenitram, TYVASO, TYVASO DPI, and Remodulin.

Orenitram® (treprostinil) Extended-Release Tablets

INDICATION

Orenitram is a prostacyclin mimetic indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).

IMPORTANT SAFETY INFORMATION FOR ORENITRAM

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 at www.orenitram.com or call 1-877-UNITHER (1-877-864-8437).

OREISIhcpOCT19

TYVASO® (treprostinil) Inhalation Solution and TYVASO DPI™ (treprostinil) Inhalation Powder

INDICATION

TYVASO (treprostinil) Inhalation Solution and TYVASO DPI (treprostinil) Inhalation Powder are prostacyclin mimetics indicated for the treatment of:

  • Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with TYVASO establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

    The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.

    While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with TYVASO was limited to 12 weeks in duration.
  • Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with TYVASO establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%).

IMPORTANT SAFETY INFORMATION FOR TYVASO AND TYVASO DPI

WARNINGS AND PRECAUTIONS

  • TYVASO and TYVASO DPI are pulmonary and systemic vasodilators. In patients with low systemic arterial pressure, either product may produce symptomatic hypotension.
  • Both products inhibit platelet aggregation and increase the risk of bleeding.
  • Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness.
  • Like other inhaled prostaglandins, TYVASO and TYVASO DPI may cause acute bronchospasm. Patients with asthma or chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment with TYVASO and TYVASO DPI.

DRUG INTERACTIONS/SPECIFIC POPULATIONS

  • The concomitant use of either product with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension.
  • Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8.
  • Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production.
  • Safety and effectiveness in pediatric patients have not been established.
  • Across clinical studies used to establish the effectiveness of TYVASO in patients with PAH and PH-ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy.

ADVERSE REACTIONS

  • Pulmonary Arterial Hypertension (WHO Group 1)
    In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most common adverse reactions seen with TYVASO in ≥4% of PAH patients and more than 3% greater than placebo were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%). In addition, adverse reactions occurring in ≥4% of patients were dizziness and diarrhea.

    In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of TYVASO who switched to a corresponding dose of TYVASO DPI, the most commonly reported adverse events seen with TYVASO DPI in ≥4% of PAH patients during the 3-week treatment phase included cough (35.3%), headache (15.7%), dyspnea (7.8%), and nausea (5.9%).
  • Pulmonary Hypertension Associated with ILD (WHO Group 3)
    In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions with TYVASO were similar to the experience in studies of PAH.

Please see Full Prescribing Information for TYVASO or TYVASO DPI, Instructions for Use manuals for TD-100 and TD-300 TYVASO® Inhalation System and TYVASO DPI™ Inhalation Powder, and additional information at www.TYVASOhcp.com or call 1-877-UNITHER (1-877-864-8437).

TYVISIhcpMAY2022

Remodulin® (treprostinil) Injection

INDICATION

Remodulin is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).

In patients with PAH requiring transition from epoprostenol, Remodulin is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

IMPORTANT SAFETY INFORMATION FOR REMODULIN

WARNINGS AND PRECAUTIONS

  • Chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.
  • Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in worsening of PAH symptoms.
  • Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function.
  • Remodulin is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension.
  • Remodulin inhibits platelet aggregation and increases the risk of bleeding.

ADVERSE REACTIONS

  • In clinical studies of SC Remodulin infusion, the most common adverse events reported were infusion site pain and infusion site reaction (redness, swelling, and rash). These symptoms were sometimes severe and sometimes required treatment with narcotics or discontinuation of Remodulin. The IV infusion of Remodulin with an external infusion pump has been associated with a risk of blood stream infections, arm swelling, paresthesias, hematoma, and pain. Other common adverse events (≥3% more than placebo) seen with either SC or IV Remodulin were headache (27% vs. 23%), diarrhea (25% vs. 16%), nausea (22% vs. 18%), rash (14% vs. 11%), jaw pain (13% vs. 5%), vasodilatation (11% vs. 5%), edema (9% vs. 3%), and hypotension (4% vs. 2%).

DRUG INTERACTIONS

  • Remodulin dosage adjustment may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn.

SPECIFIC POPULATIONS

  • In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min of ideal body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic insufficiency.
  • Safety and effectiveness of Remodulin in pediatric patients have not been established.
  • It is unknown if geriatric patients respond differently than younger patients. Caution should be used when selecting a dose for geriatric patients.
  • There are no adequate and well-controlled studies with Remodulin in pregnant women. It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.

Please see accompanying Full Prescribing Information for Remodulin.

For additional information, visit www.RemodulinPro.com or call Customer Service at 1-877-UNITHER (1-877-864-8437).

REMISIhcpMAY2021

References: 1. Kingman M, Archer-Chicko C, Bartlett M, et al. Management of prostacyclin side effects in adult patients with pulmonary arterial hypertension. Pulm Circ. 2017;7(3):598-608. 2. TYVASO [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2022. 3. TYVASO DPI [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2022. 4. Orenitram [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2023. 5. Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2021. 6. Ramani G, Cassady S, Shen E, et al. Novel dose-response analyses of treprostinil in pulmonary arterial hypertension and its effects on six-minute walk distance and hospitalizations. Pulm Circ. 2020;10(3):1–12. 7. Data on file. United Therapeutics Corporation. Research Triangle Park, NC. 8. Khan A, White RJ, Meyer G, et al. Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension. Respir Med. 2022;193:106744. 9. Kuwana M, Kohtaro A, Kinoshita H, et al. Efficacy, safety, and pharmacokinetics of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension. Pulm Circ. 2023;13(1):e12198. 10. Simonneau G, Barst RJ, Galie N, et al; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165(6):800-804. 11. Benza RL, Tapson VF, Gomberg-Maitland M, et al. One-year experience with intravenous treprostinil for pulmonary arterial hypertension. J Heart Lung Transplant. 2013;32(9):889-896.

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