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![References
Coons JC, Miller T, Simon MA, Ishizawar DC, Mathier MA. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients transitioned from parenteral or
inhaled prostacyclins: case series and treatment protocol. Pulmonary Circulation. 2016;6(1):132–5.
Gleason JB, Dolan J, Piran P, Rahaghi FF. The Rapid Initiation, Titration, and Transition from Intravenous to Oral Treprostinil in a Patient with Severe Pulmonary Arterial
Hypertension. Case Reports in Pulmonology. 2015;2015:1–3.
Kumar P, Thudium E, Laliberte K, Zaccardelli D, Nelsen A. A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. Clin Pharmacokinet
Clinical Pharmacokinetics. 2016;
Orenitram (treprostinil) [package insert]. Research Triangle Park, NC: United Therapeutics, 2014.
Pulmonary Arterial Hypertension (PAH) [Internet]. PAH-info.com. Actelion Pharmaceuticals Ltd; 2012 [cited 2016Jun16]. Available from: http://www.pah-info.com/home
Pulmonary Hypertension Fact Sheet [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2014 [cited 2016Jun16]. Available from:
http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_pulmonary_hypertension.htm
Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, et al. Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults. Chest. 2014;146(2):449–75.
Tonelli AR, Arelli V, Minai OA, Newman J, Bair N, Heresi GA, et al. Causes and Circumstances of Death in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med
American Journal of Respiratory and Critical Care Medicine. 2013;188(3):365–9.
“2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the
European Society of Cardiology (ESC) and the European Respiratory Society (ERS).” Nazzareno Galiè, Marc Humbert, Jean-Luc Vachiery, Simon Gibbs, Irene Lang, Adam
Torbicki, Gérald Simonneau, Andrew Peacock, Anton Vonk Noordegraaf, Maurice Beghetti, Ardeschir Ghofrani, Miguel Angel Gomez Sanchez, Georg Hansmann, Walter
Klepetko, Patrizio Lancellotti, Marco Matucci, Theresa McDonagh, Luc A. Pierard, Pedro T. Trindade, Maurizio Zompatori and Marius Hoeper.Eur Respir J2015; 46: 903–975. Eur
Respir J European Respiratory Journal. 2015;46(6):1855–6.](https://image.slidesharecdn.com/c6c932b9-6d38-4693-9422-991899a2745f-161007133058/75/Presentation-18-2048.jpg)
Uploaded byLibby Daugherty
Presentation
This document provides an outline and overview of transitioning patients from intravenous or inhaled treprostinil (Remodulin) therapy to oral treprostinil (Orenitram) therapy for pulmonary arterial hypertension. It describes a case series that rapidly transitioned 9 stable PAH patients from their current treprostinil treatment to oral Orenitram over 4 days. The results found that the transition was effective for most patients, though 2 required returning to their original therapy due to worsening symptoms.
Presentation
- 1. Remodulin to Orenitram: Transitioningfrom IV to Oral Treprostinil Therapy Libby Daugherty, Pharm.D. Candidate APPE 1 – Critical Care – Piedmont Atlanta Hospital June 17, 2016
- 2. Outline Pulmonary ArterialHypertension Pathology/Presentation Classification Epidemiology Prognosis Diagnosis Treatment Treprostinil Formulations Benefits and Considerations Transitioning to Oral Therapy Rationale Indications Method Case series Method Subjects Results Conclusion
- 3. Pulmonary Arterial Hypertension Progressive disease caused by narrowing or tightening of the pulmonary arteries Right side of the heart becomes enlarged due to the increased strain of pumping blood through the lungs Strain leads to symptoms of: Breathlessness Fatigue Weakness Angina Syncope
- 4. Pulmonary Hypertension Group1: Pulmonary Arterial Hypertension (PAH) Idiopathic/Sporadic (IPAH) Heritable (HPAH) Drug- or Toxin-induced Associated with (APAH) Connective tissue diseases (PAH-CTD) HIV infection (PAH-HIV) Portal hypertention Congenital heart disease (PAH-CHD) Schistosomiasis Sickle Cell Disease Group 1’: Pulmonary Veno-Occlusive Disease (PVOD) and/or Pulmonary Capillary Hemangiomatosis (PCH) Group 1’’: Persistent Pulmonary Hypertension of the Newborn (PPHN) Group 2: Pulmonary Hypertension (PH) due to Left Heart Disease Group 3: Pulmonary Hypertension (PH) due to Lung Diseases and/or Hypoxemia Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Group 4: Pulmonary Hypertension (PH) with unclear multifactorial mechanisms
- 5. Pulmonary Hypertension Group1: Pulmonary Arterial Hypertension (PAH) Idiopathic/Sporadic (IPAH) Heritable (HPAH) Drug- or Toxin-induced Associated with (APAH) Connective tissue diseases (PAH-CTD) HIV infection (PAH-HIV) Portal hypertention Congenital heart disease (PAH-CHD) Schistosomiasis Sickle Cell Disease I II III IV Limitation of usual physical activity None Mild Marked Inability Activity level that causes Dyspnea, fatigue, chest pain, presyncope None Normal physical activity Less than normal physical activity Almost any physical activity Discomfort at rest None None None Present Functional Classification
- 6.
- 7. Pulmonary Arterial Hypertension PAH is an Orphan Disease Prevalence of 15-50 cases per million Higher Prevalence among Certain Groups: Female gender (2-4x more prevalent) Systemic sclerosis (7-12%) HIV (0.5%) Sickle Cell Disease (2-3.75%) Schistosomiasis (4.6%)
- 8. Treatment Prostacyclin Analogues • Epoprostenol(Veletri) • Treprostinil (Remodulin, Tyvaso, Orenitram) • Iloprost (Ventavis) • Selexipag (Uptravi) Phosphodiesterase-5 Inhibitors • Sildenafil (Revatio) • Tadalafil (Adcirca) Endothelin Recepter Antagonists • Bosentan (Tracleer) • Ambrisentan (Letairis) • Macitentan (Opsumit)
- 9. Treprostinil Remodulin • IV Continuousinfusion • SQ Continuous infusion Tyvaso • INH QID Orenitram • PO TID
- 10. Transitioning to OralTreprostinil Rationale IV and SQ administration require continuous use of a CADD Cassette IV administration carries the risk of blood infections and sepsis SQ administration van be very painful INH administration is frequent and tedious (up to 9 inhalations QID) and can cause throat irritation/pain Candidates Clinically stable PAH patients 25-111ng/kg/min equivalent dose
- 11. Traditional Method forTransitioning from IV to PO Treprostinil Patient stabilized on IV treprostinil (Remodulin) Total daily dose of oral treprostinil (Orenitram) is calculated from the IV maintenance dose PO total daily dose (mg) = IV dose (ng/kg/min) X weight (kg) X 0.0072 Divide total daily dose by 3 for TID dosing Decrease the dose of Remodulin while simultaneously increasing the dose of Orenitram Remodulin can be reduced by up to 30ng/kg/min per day Orenitram can be increased by up to 6mg (2mg TID) per day
- 12. Titration and Transition Titration •Increased to goal (42ng/kg/min) over 96 hours • Hemodynamic stability achieved Transition • Orenitram started at 2mg PO TID • Increased by 2mg TID every day (every 3 doses) • Remodulin decreased by 14 ng/kg/min every 3 doses of Orenitram • Monitor for 24 hours, then discharge
- 13. Case Series Oraltreprostinil for the treatment of pulmonary arterial hypertension in patients transitioned from parenteral or inhaled prostacyclins: case series and treatment protocol Efforts to improve patient tolerability and reach optimal dosing have resulted in administration requirements and titration schedules that can be relatively complex. Data to guide the transition from parenteral/topical to oral prostacyclin therapy is limited.
- 14. Method Inclusion Criteria PAHGroup 1 Stable patients with improved symptoms/functional capacity Maintained on treprostinil IV, SQ or INH With or without background therapy Who cannot tolerate IV administration due to infection Who cannot tolerate SQ administration due to pain Who have a preference for oral therapy based on lifestyle factors Procedure Inpatient admission Right Heart Catheterization to establish a pre- transition baseline Transition over 4 days Orenitram titrated at 0.5 or 1mg TID per day depending on the maintenance dose Remodulin decreased by 10ng/kg/min per day Tyvaso decreased by 3 breaths QID per day Target dose = 10mg TID (equivalent to 40- 50ng/kg/min) upon discharge
- 15. Subjects Variety ofconcomitant background therapy with PDE-5i, ERA or combination Stable on pre-transition maintenance dose for at least 30 days Median maintenance dose before transition = 42 ng/kg/min Total daily dose calculated for each patient according to weight, maintenance dose and bioavailability Divided by 3 for TID dosing Rounded to the nearest 0.5mg Characteristic Value No. patients (F/M) 9 (7/2) Age (years) 50 (34-72) Body weight (kg) 74.8 (50.9-115.7) Type of PAH IPAH 5 PAH-CTD 2 PAH-CHD 2 WHO Functional Class 2 7 3 2 Reason for transition Intolerance of IV d/t infection 1 Intolerance of SQ d/t pain 4 Patient preference 4 Concomitant Therapy PDE5i Monotherapy 5 ERA Monotherapy 1 PDE5i/ERA Combination 2 No background therapy 1
- 16. Patient Initial TRE dose/route Initiation (mg) Discharge (mg) Lastclinic visit (mg) Clinical worsening Conversion failure 1 40 ng/kg/min SQ 1 TID 10 TID 10.25 QID Yes, mild increase in sx, decline in 6MWD, increase in BNP level No 2 12 breaths QID INH 0.5 TID 2.5 TID 7 QID No No 3 24 ng/kg/min SQ 0.5 TID 3.5 TID 2 BID No No 4 50 ng/kg/min IV 1 TID 10 TID 10 QID No No 5 40 ng/kg/min SQ 1 TID 8 TID 7 TID No No 6 70 ng/kg/min SQ 1 TID 13 TID NA, discont. Yes, syncopal episode, decreased energy and exercise tolerance Yes, resumed SQ at higher dose d/t clinical worsening and ADR 7 39 ng/kg/min IV 1 TID 8.5 TID NA, discont. No Yes, resumed SQ at baseline 8 36 ng/kg/min QS 0.5 TID 5 TID 8 TID No No 9 12 breaths QID INH 1 TID 4 TID NA, discont. d/t hospice No No
- 17. Conclusion Orenitram addsto the growing number of therapeutic options for patients with PAH Precise application the treatment of PAH is not yet firmly established Rapid transition over 4-day period appears reasonable and effective Evidence suggests that it may serve an important role in prostacyclin transitions in carefully selected, stable patients who are receiving background therapy. Ongoing clinical trials will evaluate long-term effects, quality of life, disease progression and survival. Further study is needed regarding frequency of administration
- 18. References Coons JC,Miller T, Simon MA, Ishizawar DC, Mathier MA. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients transitioned from parenteral or inhaled prostacyclins: case series and treatment protocol. Pulmonary Circulation. 2016;6(1):132–5. Gleason JB, Dolan J, Piran P, Rahaghi FF. The Rapid Initiation, Titration, and Transition from Intravenous to Oral Treprostinil in a Patient with Severe Pulmonary Arterial Hypertension. Case Reports in Pulmonology. 2015;2015:1–3. Kumar P, Thudium E, Laliberte K, Zaccardelli D, Nelsen A. A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. Clin Pharmacokinet Clinical Pharmacokinetics. 2016; Orenitram (treprostinil) [package insert]. Research Triangle Park, NC: United Therapeutics, 2014. Pulmonary Arterial Hypertension (PAH) [Internet]. PAH-info.com. Actelion Pharmaceuticals Ltd; 2012 [cited 2016Jun16]. Available from: http://www.pah-info.com/home Pulmonary Hypertension Fact Sheet [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2014 [cited 2016Jun16]. Available from: http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_pulmonary_hypertension.htm Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, et al. Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults. Chest. 2014;146(2):449–75. Tonelli AR, Arelli V, Minai OA, Newman J, Bair N, Heresi GA, et al. Causes and Circumstances of Death in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med American Journal of Respiratory and Critical Care Medicine. 2013;188(3):365–9. “2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS).” Nazzareno Galiè, Marc Humbert, Jean-Luc Vachiery, Simon Gibbs, Irene Lang, Adam Torbicki, Gérald Simonneau, Andrew Peacock, Anton Vonk Noordegraaf, Maurice Beghetti, Ardeschir Ghofrani, Miguel Angel Gomez Sanchez, Georg Hansmann, Walter Klepetko, Patrizio Lancellotti, Marco Matucci, Theresa McDonagh, Luc A. Pierard, Pedro T. Trindade, Maurizio Zompatori and Marius Hoeper.Eur Respir J2015; 46: 903–975. Eur Respir J European Respiratory Journal. 2015;46(6):1855–6.
Editor's Notes
- #3 Periwinkle Ribbon Stomach cancer Esophageal cancer Eating disorders Anorexia Bulimia EDNOS Pulmonary hypertension
- #5 IPAH Sporadic disease No family history of PAH No identified risk factor HPAH Various mutations (BMPR2 (Bone Morphogenetic Protein Receptor 2)= 80% of these) APAH Connective tissue diseases (PAH-CTD) Systemic sclerosis (SSc) Systemic lupus erythematosus (SLE) HIV infection (PAH-HIV) Rare but well documented Portal hypertention Complication of liver disease Rare but well documented Portopulmonary hypertension Congenital heart disease (PAH-CHD) Congenital shunts (especially Eisenmenger’s syndrome, right left shunt) Can persist even after corrective surgery Schistosomiasis Parasitic disease caused by trematode flatworms Chronic hemolytic anemia Drug- or Toxin-Induced Rare side effect of some appetite suppressants (anorexigenic agents) Definite Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Benfluorex SSRIs Likely Amphetamines Dasatinib L-tryptophan Methamphetamines Possible Cocaine Phenylpropanolamine St. John’s Wort Interferon Cyclophosphamide and similar Groups 1’ and 1’’ have distinct etiologies from Group 1, but are still primary disease Groups 2-5 are types of PH caused by another disease state (PH is secondary to something else) PAH treatment usually not indicated in these groups (except for Group 4) Underlying cause is treated instead
- #6 Any signs of right sided heart failure = FC IV
- #7 Diagnostic Gold Standard PAH Characterized by: Mean pulmonary arterial pressure (mPAP) ≥ 25mmHg at rest Mean Pulmonary capillary wedge pressure (PCWP) ≤ 15mmHg
- #8 Population of USA = ~320 million 48,00 – 16,000 PAH patients in the US Orphan Disease = affects < 200,000 nationwide Population of Atlanta metro area = ~5.5 million 82.5 - 275 (<300 PAH patients in Atlanta) 2 PAH cases in 4 East ICU right now Survival Without therapy 1 year: 68% 3 years: 48% 5 years: 34% With therapy 1 year: 83% 3 years: 58%
- #9 No cure for PAH 3 classifications of drugs to treat advanced PAH (Group II-IV) Can slow progression, treat symptoms and improve quality of life Prostacyclin pathway (Prosacyclin analogs) Prostacyclin low levels in patients with PAH potent vasodilator inhibitor of platelet activation Activation of adenylate cyclase = increase in cAMP therapy with prostacyclin or prostacyclin analogues can help to correct this deficiency The only class that improves mortality Nitric Oxide pathway (PDE-5 inhibitors) Nitric oxide potent vasodilator possesses anti-proliferative properties impaired production in PAH vasodilatory effect is mediated by cGMP rapidly degraded by phosphodiesterases (PDEs) into GMP therapy with oral PDE-5 inhibitors reduces degradation Endothelin pathway (ERAs) Endothelin-1 (ET-1) elevated levels are seen in PAH patients levels correlate with disease severity deleterious effects mediated through ETA receptors Fibrosis Hypertrophy and cell proliferation Inflammation Vasoconstriction ETB receptors do the opposite, much weaker Endothelin receptor antagonists can block these effects
- #10 Treprostinil is a prostacyclin analogue Benefits Multiple formulations Long half life (4hr compared to 6min with Veletri) 48 hour stability at room temp (vs 24hr with Veletri) Negatives Takes longer to titrate than veletri
- #11 Rationale: Intolerance or Patient Preference CADD Cassettes have to be changed every 48 hours and are cumbersome Preliminary data from a study evaluating the safety, tolerability, pharmacokinetics, and logistics of transitioning clinically stable PAH patients from parenteral (25–111 ng/kg/min) to oral treprostinil indicates that the transition is feasible in the majority of subjects. Orenitram (Treprostinil Diolamine) available in multiple strengths: 0.125 0.25 1 2.5
- #12 Current PAH guidelines (CHEST 2014, ESC/ERS 2015) offer no specific guidelines for transitioning from parenteral to oral treprostinil Current method for transitioning is based on the Orenitram package insert Oral daily dose based on the patient’s weight and the oral bioavailability of Orenitram 0.0072 is a correction factor for bioavailability and unit conversion Before transition May already be at goal May require titration up to goal TID dosing is preferred to BID dosing
- #13 From a case report: The Rapid Initiation, Titration, and Transition from Intravenous to Oral Treprostinil in a Patient with Severe Pulmonary Arterial Hypertension Initial Titration Started at 4ng/kg/min Increased by 4ng/kg/min Q8H Developed hypotension requiring PE around 36 hours (20ng/kg/min) Unrelated to PAH Infectious cause Resolved with broad spectrum antibiotics Increased to 42 ng/kg/min (goal) over 96 hours Hemodynamic stability demonstrated Transition PO Started at 2mg PO TID Dose increased by 2mg TID every day (ever 3 doses, the dose was increased by 2mg) maximum suggested by package insert IV Started at baseline of 42 ng/kg/min Dose decreased by 14 ng/kg min 1 hour after every PO dose increase 42 28 at HR1 (Day 0) 28 14 at HR25 (Day 1) Stayed at 14 for HR 49 (Day 2) 14 0 at HR73 (Day 3) Monitored for 24 hours (Day 4) after goal achieved, then discharged home
- #15 No mention of exclusion criteria
- #16 PAH-CHD patients: Ventricular septal defect repair Late atrial septal defect closure
- #17 6/9 patients started on 1mg TID, 3/9 on 0.5mg TID Median dose at discharge was 8mg TID (24mg total daily dose) 7/9 patients achieved a successful transition 1 patient discontinued d/t clinical worsening and significant ADRs 1 patient discontinued d/t ADRs 1 patient had clinical worsening, but was able to continue at a higher dose 6/9 patients had clinical follow-up at 47 weeks 1 D/C due to hospice, but had successfully transitioned Median dose at follow-up was 28mg total daily 6MWD data for 4/6 follow-up patients 2 improved 403 412m @ 10 months 407 403m @ 6 months 2 declined 515 457m @ 10 months 311 256, @ 6 months 8/9 patients experienced ADRs, mostly GI-related 2 patients had to reduce their dose after discharge d/t ADR Other 5 had increases in dose No obvious correlation between concomitant background therapy and ADR The 1 patient who did not have ADR was on combination PDE-5i/ERA Dosing frequency adjusted to minimize ADR Based on DLT 2 patients remained on TID 3 patients increased to QID 1 patient reduced to BID Oral QID dosing has not been studied/reported, but in each case the patient was better able to tolerate the medication at a higher daily dose PK and clinical outcomes need further investigation