Introduction
Yutrepia™ (treprostinil) inhalation powder is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH). It is a dry powder formulation administered via a handheld inhaler, representing an advancement in prostacyclin therapy that offers greater convenience and portability compared to traditional nebulized formulations. Yutrepia is designed to improve exercise capacity in patients with WHO Group 1 PAH.
Mechanism of Action
Treprostinil, the active component of Yutrepia, binds to prostacyclin receptors on vascular endothelium and platelets. This binding activates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) levels. The resulting pharmacological effects include:
- Potent direct vasodilation of pulmonary and systemic arterial beds
- Inhibition of platelet aggregation
- Antiproliferative effects on vascular smooth muscle cells
- Anti-inflammatory properties
These actions collectively reduce pulmonary vascular resistance, decrease right ventricular afterload, and improve cardiac output in PAH patients.
Indications
Yutrepia is indicated for:
- Treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise capacity in adults
- Patients with NYHA Functional Class II-III symptoms
The efficacy was established primarily in patients with idiopathic or heritable PAH, PAH associated with connective tissue diseases, and PAH associated with congenital heart disease with repaired shunts.
Dosage and Administration
Initial Dosing: 3 breaths (54 mcg) four times daily Titration: Increase by 3 breaths (54 mcg) per dose approximately every 3-7 days as tolerated Maintenance Dose: Individualized based on clinical response and tolerability; typical range is 12-24 breaths (216-432 mcg) four times daily Maximum Dose: 12 breaths (216 mcg) per dose (864 mcg daily) Administration Instructions:- Administer at approximately 4-hour intervals during waking hours
- Use the provided breath-actuated inhaler device
- Prime the device before first use and if not used for more than 3 days
- Rinse mouth after administration to prevent cough and potential tooth damage
- Hepatic impairment: Reduce initial dose and titrate cautiously
- Renal impairment: No specific dosage adjustment recommended
- Elderly: Use caution due to increased likelihood of hepatic, renal, or cardiac impairment
Pharmacokinetics
Absorption: Rapidly absorbed following inhalation; peak plasma concentrations achieved within approximately 15-30 minutes Distribution: Steady-state volume of distribution approximately 14-18 L/kg; 91% plasma protein bound Metabolism: Primarily hepatic via CYP2C8 with minor contribution from CYP2C9; extensive metabolism to inactive metabolites Elimination: Primarily renal (79% of dose) with 13% fecal elimination; terminal half-life approximately 2-4 hours Bioavailability: Approximately 72% following inhalation administrationContraindications
- Hypersensitivity to treprostinil or any component of the formulation
- Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) due to significant increases in treprostinil exposure
Warnings and Precautions
Pulmonary Hypertension Deterioration: Abrupt discontinuation or sudden large reductions in dosage may result in worsening of PAH symptoms Pulmonary Edema: Has been reported in patients with pulmonary veno-occlusive disease; discontinue if signs occur Bronchospasm: May cause bronchoconstriction; use with caution in patients with asthma or COPD Bleeding Risk: Inhibits platelet aggregation; increased risk of bleeding, particularly in patients on anticoagulants Hypotension: May cause symptomatic hypotension; use caution in patients with low systemic arterial pressure Hepatic Impairment: Increased exposure in hepatic impairment; reduce dose and monitor closely Inhalation-Related Effects: May cause cough, throat irritation, and bronchospasmDrug Interactions
Strong CYP2C8 Inhibitors (e.g., gemfibrozil): Contraindicated due to potential for significantly increased treprostinil exposure CYP2C8 Inducers (e.g., rifampin): May decrease treprostinil concentrations; monitor and adjust dose as needed Antihypertensive Agents: Additive hypotensive effects; monitor blood pressure Anticoagulants: Increased risk of bleeding; monitor coagulation parameters closely Diuretics: Enhanced hypotensive effects; monitor fluid status and blood pressureAdverse Effects
Most Common Adverse Reactions (≥10%):- Cough (69%)
- Headache (39%)
- Throat irritation (25%)
- Nausea (14%)
- Flushing (13%)
- Dyspnea (12%)
- Pulmonary edema
- Significant hypotension
- Syncope
- Hemoptysis
- Bronchospasm
- Right ventricular failure
Monitoring Parameters
- Exercise capacity (6-minute walk distance)
- WHO functional class assessment
- Signs and symptoms of PAH progression
- Blood pressure (particularly during dose titration)
- Oxygen saturation
- Hepatic function (baseline and periodically)
- Bleeding parameters in patients on anticoagulants
- Inhalation technique and device use
- Signs of pulmonary edema
Patient Education
- Use Yutrepia exactly as prescribed; do not discontinue abruptly
- Maintain a consistent dosing schedule approximately every 4 hours while awake
- Learn proper inhaler technique from healthcare provider
- Rinse mouth with water after each dose to prevent mouth and throat irritation
- Report any worsening of PAH symptoms (increased shortness of breath, dizziness, fatigue)
- Inform all healthcare providers about Yutrepia use, particularly before surgery
- Be aware of potential side effects including cough, headache, and flushing
- Keep the inhaler dry and clean; store in a dry place
- Use caution when driving or operating machinery until effects are known
- Inform healthcare provider if pregnant, planning pregnancy, or breastfeeding
References
1. FDA Approval Package: Yutrepia™ (treprostinil) inhalation powder. NDA 214959. 2. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease. N Engl J Med. 2021;384(4):325-334. 3. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65(18):1976-1997. 4. Yutrepia Prescribing Information. Liquidia Technologies, Inc.; 2023. 5. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. 6. Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012;142(6):1383-1390.
This monograph is for educational purposes only. Healthcare providers should consult the full prescribing information and clinical guidelines for complete treatment recommendations.